Substituted-3,5-seco-a-nor-pregnan-3-oic acids

ABSTRACT

THIS INVENTION IS DIRECTED TO SUBSTITUTED-3,5-SECO-ANORPREGNAN-3-OIC ACIDS AND DERIVATIVES THEREOF WHICH ARE USEFUL AS INTERMEDIATES IN THE SYNTHESIS OF KNOWN 9B,10ASTEROIDS OF THE PREGNANE SERIES. THE LATTER COMPOUNDS CAN BE UTILIZED AS BOTH PROGESTATIONAL AND SALT-RETAINING AGENTS.

United States Patent O ABSTRACT OF THE DISCLOSURE This invention is directed to substituted-3,5-seco-A- norpregnan-3-oic acids and derivatives thereof which are useful as intermediates in the synthesis of known 95,100:- steroids of the pregnane series. The latter compounds can be utilized as both progestational and salt-retaining agents.

RELATED APPLICATIONS This application is.a division of applicants copending application Ser. No. 736,568, filed June 13, 1968, which is a division of applicants copending application Ser. No. 499,094, filed Oct. 20, 1965, entitled Intermediates and Processes, now US. Pat. 3,574,761, dated Apr. 13, 1971, which is a continuation-in-part of applicants copending application Ser. No. 400,206, filed Sept. 29, 1964, entitled Intermediates and Processes, now US. Pat. No. 3,412,- 107, issued Nov. 19, 1968.

DETAILED DESCRIPTION OF THE INVENTION This invention relates to novel chemical intermediates and processes useful in the preparation of steroids. Natural steroids possess a 9a,1018-stereochemica1 configuration. Steroidal compounds possessing the unnatural 913,10a-configuration represent a pharmaceutically valuable class of compounds which, even though numerous members are known in the art, cannot be obtained by totally classical chemical means. In fact, the only known methods for obtaining steroids possessing the unnatural 9/3,l0a-configuration involve at least one photochemical reaction. Such photochemical reactions involve irradiation with ultraviolet light of strong intensity for long periods of time and, in comparison with purely chemical reactions, are very inefiicient and give only small yields.

It is an object of the present invention to provide intermediate and processes which enable the preparation of 9fl,10u-steroids without the necessity of proceeding through a photochemical reaction. It is also an object of this invention to provide novel intermediates and processes which will enable the further exploration of steroids having the unnatural 9,8,10a-configuration. It is also an object of this invention to provide novel 9 3,la-steroids.

The novel intermediates and processes of this invention are valuable and provide a new synthetic route completely of a classical chemical nature, i.e. involving no photochemical reaction, for converting steroids having the normal configuration into steroidal compounds possessing the unnatural 9 3,10u-configuration.

In one aspect, the novel intermediates and processes 3,766,256 Patented Oct. 16, 1973 of this invention enable the preparation of 9,6,l0a-steroids of the androstane series of the formula wherein R is, individually, selected from the group consisting of hydroxy and lower alkanoyloxy; R is, individually, hydrogen or lower alkyl and R and R taken together, are selected from the group consisting of (17;?- OH, 17a-1OW61 alkanoic acid lactone) and 0x0; R is selected from the group consisting of hydrogen, lower alkyl, hydroxy and lower alkanoyloxy; Y is selected from the group consisting of hydrogen and lower alkyl and X is a substituent in the 6- or 7-position selected from the group consisting of hydrogen, lower alkyl, lower alkylthio, lower alkanoylthio and halogen.

Compounds of Formula I are useful as anabolic agents.

Other 9fi,10u-androstanes, the prepaartion of which is enabled by the intermediates and processes of this invention, are of the formulae wherein R R;,, Y and X have the same meaning as above. Compounds of Formula III are useful as progestational agents and compounds of Formula II are useful as anti-androgenic agents.

In another embodiment of this invention, the novel compounds and intermediates provided by this invention CHz-Rs wherein Y and X have the same meaning as above;

R' is selected from the group consisting of hydrogen, lower alkyl, fluoro, hydroxy and lower alkanoyloxy; R is selected from the group consisting of hydrogen and halogen; and R is selected from the group consisting of hydrogen, lower alkyl, hydroxy and halogen. Compounds of Formula IV are useful as progestational agents.

Other 918,10a-steroids of the l7fl-pregnane series, preparable from the novel compounds and process of this invention, are of the formula CHIOH wherein R;,-, R Y and X have the same meaning as above.

Compounds of Formula V are useful as salt-retaining agents, i.e. are useful in the treatment of Addisons disease.

As used herein, the term lower comprehends both straight and branched chain saturated hydrocarbon groups, such as methyl, ethyl, propyl, isopropyl and the like. Similarly, the term lower alkanoyl comprehends groups such as acetyl and the like, and the term lower alkanoyloxy comprehends groups e.g. formyloxy, acetoxy and the like. In the same manner, the term lower alkenyl comprehends groups such as vinyl and the like, and the term lower alkynyl comprehends groups such as ethinyl and the like. Halogen comprehends all four halogens, i.e. iodine, bromine, chlorine and fluorine.

The expression (17,8-OH, 17oc-1OW61 alkanoic acid lactone) refers to a configuration on the C-l7 carbon atom illustrated as follows:

wherein W is lower alkylene, e.g.

polymethylenes such as ethylene, propylene or the like.

With respect to substitutents in the 6- and 7- position, preferred compounds are those having hydrogen or lower alkyl in 6- or 7-position, and those having halogen in the 7-position.

In one aspect, this invention comprises a method for the preparation of 9B,10u-androstanes of Formulae 1-111 and of 95,l0a-17;8-pregnanes of Formulae IV-V which comprises the hydrogenation Of desA-andros nor of desA-l7-pregn-9-en-5-ones to 9,8,10,6-desA-androyields the desired 9fl,10a-steroids. The symbol Q is bro-.

mine, chlorine or iodine, with the former two being preferred. This invention also provides a number of different methods for the preparation of said desA-androst-9-en-5- one or desA-17B-pregn-9-en-5-one starting materials from natural steroids.

In one embodiment, a steroid of the 3-oxo-androst-4- ene or 3-oXo-l7/3pregn-4-ene series is subjected to an oxidative ring opening of the A-ring yielding a 5-oxo-3,5- seco-A-norandrostan-3-oic acid or a 5-oXo-3,5-seco-A-norl7fi-pregnane3-oic acid, which 3-oic acid can then be converted to a mixture of a l0a-desA-androstan-5-one and a IOB-desA-androstan-S-one or a mixture of a 10u-desA- l7fl-pregnan-5-one and a lO S-deSA-17fl-pregnan-5-one. The conversion of the 3-oic acid to the desA-compound can be effected either by pyrolysis of a salt of said 3-oic acid or via the enol lactone, i.e. a 4-oxoandrost-5-en-3- "can be effected in a variety of ways. In one approach, an

ll-hydroxy group of a steroid of the 3-oxo-androst-4-ene or 3-oxo-l7fi-pregn-4-ene series is converted. into a leaving group, for example, a sulfonic acid ester or carboxylic acid ester. Oxidative ring opening of the A-ring of the thus formed ll-(esterified hydroxy)-containing compound yields the corresponding ll-(esterified 'hydroxy)-5-oxo- 3,5-seco-A-norandrostan-3-oic acid or ll-(esterified hydroxy) 5 0x0 3,5 seco A-nor-l7fi-pregnan-3-oic acid which upon pyrolysis of a salt of said 3-oic acid yields the'desired desA-androst-9-en-5-one or desA-l7flpregn- 9-en-5-one starting material.

A further approach involves formation of an ll-hydroxy-desA-androstan 5 one or 11-hydroxy-desA-l7/8- pregnan-S-one from an ll-hydroxy steroid of the 3-oxoandrost-4-ene or 3-oXo-l7B-pregn-4-ene series via an oxidative ring opening of the A-ring of said ll-hydroxy steroid which yields an 1l-hydroxy-5-oxo-A-nor 3,S-secoandrostan-3-oic acid 3,11-lactone or an ll-hydroxy-S- oxo-3,5-seco-17B-pregnan-3-oic acid 3,11-lactone which, in turn is converted into a salt of the corresponding keto acid which salt upon pyrolysis gives the 11-hydroxy-desA- androstan-S-one or 1l-hydroxy-desA-17,8-pregnan-5-one. Esterification of the ll-hydroxy moiety of the so-obtained compound with an acid moiety yields an ll-(esterified hydroxy)-desA-androstan-5-one or an ll-esterified hydroxy)-desA-17fl-pregnan-5-one which upon elimination of the leaving group (i.e., the esterified hydroxy moiety) gives the desired desA-androst-9-en-5-one or desA-l7fipregn-9-en-5-one starting material. Though, in the above.

reaction sequence either Ila-OH or llfl-OH starting material steroids can be used, it is preferred to use Ila-OH quences of this invention involve any modification of substituents found in the 16- and/or l7-position of the starting material natural steroids. However, in order to obtain unnatural 9fi,l0a-steroids of Formulae I-V, it is necessary or desirable to protect certain of the 16- and/or 17-substituents against one or more of the reaction steps involved. It is also convenient to initially protect such a substituent in the starting material natural steroid and maintain the substituent in its protected form throughout the entire reaction sequence, regenerating the desired substituent only when the steroid of Formula IV possessing the unnatural 9fl,10a-configuration is obtained. On the othre hand, it is sometimes convenient to insert a protecting group only before a certain reaction step or sequence of reaction steps. Said protecting group can then be maintained until the final reaction step or can be split ofi? at some intermediate stage. The protecting groups can be inserted and split off by means known per se. The desirability of having protecting groups present will be further discussed below when the specific reaction steps are discussed in detail. The various substituents which are susceptible to being protected are exemplified by the 16- hydroxy group in a compound of any of Formulas I-V, the 17,8-hydroxy group in a compound of any of Formulas I-III, the 17a-hydroxy or 20-oxo group in a compound of any of Formulas IV-V, the 2l-hydroxy group of a compound of Formula V or the 17-oxo group of a compound of Formula I.

The 17-oxo or 20-oxo group is suitably protected by ketalization, i.e., by reaction with a lower al'kanediol, to yield a l7-lower alkylene dioxy or 20-lower alkylene dioxy compound, i.e., a 17-ketal or a ZO-ketal.

The 16-hydroxy, 17a-hydroxy, 17B-hydroxy or 21- hydroxy moieties can be protected by esterification and/ or etherification of the hydroxy group. Any available acid which will form an ester that can subsequently be hydrolyzed to regenerate the hydroxy group is suitable. Exemplary acids useful for this purpose are lower alkanoic acids, e.g. acetic acid, caproic acid, benzoic acid, phosphoric acid and lower alkane dicarboxylic acids, e.g. succinic acid. Also, protection for the l6a-hydroxy, 17a-hydroxy, or 21-hydroxy substituent can be efiected by forming the lower alkyl ortho ester thereof, i.e. l6cc,17aor 17a,21-lower alkyl ortho esters. A suitable ether protecting group is, for example, the tetrahydropyranyl ether. Others are arylmethyl ethers such as, for example, the benzyl, benzhydryl and trityl ethers, or a-lower alkoxylower alkyl ethers, for example, the methoxymethyl, or allylic ethers.

In compounds containing the dihydroxyacetone side chain at -C17 (for example, compounds of Formula V wherein R is hydroxy), the side chain at (1-17 can be protected by forming the 17,20; 20,2l-bis-methylenedioxy group or by forming a 17,21-acetal or ketal group, or by forming a 17,20-diester. The 17,21-acetal or ketal and 17,21-diester hinder the 20-ketone group and minimize the possibility of its participating in unwanted side reactions. On the other hand, the 17,20;20,2l-bis-methylenedioxy derivatives actually convert the ketone, to a nonreactive derivative. When both a 16a-hydroxy and 17ahydroxy substituent are present, these groups can be protected via formation of a 16a-l7a-acetal or ketal. The various protecting groups mentioned above can be removed by means known per se, for example, by mild acid hydrolysis.

In compounds wherein there is present neither a 170:- hydroxy nor 21-hydroxy substituent but there is present a 20-oxo group, the 20-oxo group can be protected via reduction to the corresponding carbinol (hydroxy) group. Thus, for example, the 17-acetyl side chain can be protected via conversion to a 17-(a-hydroxyethyl)-side chain. Regeneration of the l7-acetyl side chain can be simply effected via conventional oxidation means, for example, via oxidation with chromium trioxide in an organic solvent such as glacial acetic acid. Similarly in compounds containing a l7-oxo, this group can be protected by reduction to the corresponding carbinal (hydroxy) group. Thus, the 17-oxo grou can be reduced to a 17,8- OH, 17oc-H moiety, from which, when desired, the l7-oxo moiety can be regenerated by oxidation, as described above. Furthermore, a 20-hydroxy or flit-hydroxy group, can itself be protected by esterification, for example, with a lower alkanoic acid such as acetic acid, caproic acid, or the like; or by etherification with moieties such as tetrahydropyranyl, benzyl, benzhydryl, trityl, allyl, or the like.

The 16a-17u or 17a,21-aceta1s and ketals above discussed can be formed by reacting 16a,17u-bis-hydroxy or 17a,21-ibis-hydroxy starting materials with an aldehyde or a ketone; preferably it is done by reacting a simple acetal or ketal (i.e. a lower alkylene glycol acetal or ketal of a suitable aldehyde or ketone) with the moieties sought to be protected.

Suitable aldehydes and ketones include lower alkanals of at least two carbon atoms, such as paraldehyde, propanal and hexanal; di(lower alkyl)ketones, such as acetone, diethylketone, dibutylketone, methylethylketone, and methylisobutylketone; cycloalkanones, such as cyclobutanone, cyclopentanone and cyclohexanone; cycloalkyl (lower alkanals), such as cyclopentylcarboxaldehyde and cyclohexylcarboxaldehyde; cycloalkyl lower alkyl ketones, such as cyclopentyl propyl ketone, cycloh'exylmethyl ethyl ketone; dicycloalkyl ketones, such as dicyclopentyl ketone, dicyclohexyl ketone and cyclopentyl cyclohexyl ketone; cycloalkyl monocyclic aromatic ketones, such as cyclohexyl p-chlorophenyl ketone, cyclopentyl o-methoxyphenyl ketone, cyclopentyl o,p-dihydroxy-phenyl ket-one and cyclohexyl m-tolyl ketone; cycloalkyl-lower alkyl monocyclic aromatic ketones, such as cyclopentylmethyl phenyl ketone; cycloalkyl monocyclic aromatic-lower alkyl ketones, such as cyclopentyl benzyl ketone and cyclohexyl phenethyl ketone; cycloalkyl-lower alkyl monocyclic aromatic-lower alkyl ketones, such as cyclopentylmethyl benzyl ketone; halolower alkanals, such as chloral hydrate, trifluoroacetaldehyde hemiacetal, and heptafiuorobutanal ethyl hemiacetal; halo-lower alkanones such as 1,1,l-trifiuoroacetone; monocyclic carbocyclic aromatic aldehydes, such as benzaldehyde, halobenzaldehydes (e.g. p-chlorobenzaldehyde and p-fluorobenzaldehyde), lower alkoxy-benzaldehydes (e.g. o-anisaldehyde), di(lower alkoxy)benzaldehydes (e.g. veratraldehyde), hydroxybenzaldehydes (e.g. salicylaldehyde), lower alkyl benzaldehydes (e.g. m-tolualdehyde and p-ethylbenzaldehyde), di(lower alkyl)- benzaldehydes (e.g. o-p-dimethylbenzaldehyde); monocyclic carboxylic aromatic lower alkanals, such as phenylacetaldehyde, a-phenylpropionaldehyde, fl-phenylpropionaldehyde, 4-phenylbutyraldehyde, and aromaticallysubstituted halo, lower alkoxy, hydroxy and lower alkyl cyano derivatives thereof; monocyclic carbocyclic aromatic ketones, such as acetophenone, a,a,a-trifiuoroacetophenone, propiophenone, butyrophenone, valerophenone, halophenyl lower alkyl ketones (e.g. p-chloroacetophenone and p-chloropropiophenone); (lower alkoxy) phenyl lower alkyl ketones (e.g. p-anisyl methyl ketone); di-(lower alkoxy) phenyl lower alkyl ketones; hydroxyphenyl lower alkyl ketones; (lower alkyl)phenyl lower alkyl ketones (e.g. methyl p-tolyl ketone); di(lower alkyl) phenyl lower alkyl ketones (o,p-xylyl methyl ketone; benzophenone, and mono-or bis-substituted halo, lower alkoxy, hydroxy and lower alkyl derivatives thereof; monocyclic carbocyclic aromatic lower alkanones, such as 1-phenyl-3-butanone and l-phenyl-4-pentanone, and aromatically substituted derivatives thereof.

Especially suitable are those aldehydes or ketones which, with the :,17aor 17a,21-'bis-hydroxy grouping form an acetal or ketal group of the formula wherein R2; and'X have V wherein R R and X sisting of hydrogen and 'lo wer alkylj Q is individually selected from the group. consisting of lower alkyl and aryl; and; P andQ'taken' together are lower alkylene.-

The term -lower alkylene comprehends polymethylenechains such as tetramethylene and'pentamethylene.

In discussing the various starting materials, intermediates and end-products of this invention, the various protecting groups discussed above will not necessarily be specifically mentioned, but it should beund'erstood that mention of any substituent comprehends the various protected forms thereof, unless specifically mentioned to the l g contrary;

In one embodiment of this invention, compounds of Formulas I through V are prepared from 95,10,8-desA- androstan-S-ones or 93,IQB-desA-pregnan-S-ones of the formula V A 3,766,256 wherein ?is individually. sewer from con- Moreover, ,QB JOe UfiQregnanes o'rfFormnlae IV and a i] can be prepared from 93,105

stituents in the 1.6- and 17-positions, as defined intFor-f mulae I-V above.

Thus,l9 3,10u-androstanes rof Formula I. can be prepared;

from 9fi,10fl-desA-androstan-5 -ones of theformula '(VII) the same meaning as above." 7

Similarly, 9B,10a-androstanes of Formula II canbe pre-;

i paredi from 913,10,8-desA-androstan-S-ones,t of a Formula have the same meaning as above.

Formulae and XI, respectively. 7 l 1 VCHrR.

wherein R above.

The conversion of a 95,10,8-desA-compound of For- I mula VI to a 95,10a-steroid of Formulae I-V (i.e., VII- 1, VIII- II,- IX III, X IV and XI- V) is effected 'butan-3 one lower alkylene 'ketal, 1-Q-butan-3-ol', l-Q-butan-3-ol ether, esterified l-Q-butan-3-bl, l-Q-pentan-lt-one, l-Q-pentan-3-one lower alkylene ketal, '1-Q-pentan-31-o1, l-Q-pentan-3 ol ether or esterified l-Q-pentan-3-ol, Q is "bromo; chloro oriodo-,'with' the'former two being pre-- l ferred. Methyl vinyl ketone and l-tertiary amino-S-butanone are the preferred reagents, and the former is es- 7 pecially preferred. Prior to the condensation it is desirable 'f to" protect the" 20-keto group present in compounds of FormulaelX and XI, then it is not necessary to protect 1 6a,

171: or 21-hydroxy groups which are present, but groups protecting these moieties can be retained through the condensation'reaction. V i The above indicated substitutes for lower alkyl vinyl ketones are compounds wherein the vinyl moiety is replaced by a moiety of the formula N-CHz-CHrwherein eachR is lower alkyl or taken together both Rs are lower alkylene oxa-lower alkylene or aza-lower 7 I alkylene." Such moieties are, for example, dimethylamino; r, diethylamino, ,pyrrolidino, piperid-ino, morpholino, or thev 1 like. The quaternary ammonium; salts thereof are formed via theutilization of conventional quaternizing agents, r for example, lower alkyl. or phenyl-lower alkyl {especially benzyl) halides, mesylatesl or tosylates.

When a lower alkyl vinyl ketone, or substitute there-' 7 k for, l Q-biitan-S one or l-Q-pentan-3 one is. used as the simultaneously with the condensation; However, when 1,3-di

flower; alkylene ketal, '75

tehlorobut-2-ene, 1,3'-dichl0ropent-2-ene,, l-Q-butamB-one I 1-Q-butan3-ol, 1-Q-butan-3-ol" ether, "esterified' l-Q-butan-Zl-ol, I-Q-pentan-S-one lower -desA-pregnan-5-ones of R5, R and X have the same meaning as v alkylene ketal, l-Q-pentan-S-ol, 1-Q-pentan-3- ol ether, or esterified l-Q-pentan-S-ol is used as the reaction partner a subsequent step to generate the 3-oxo moiety is required. When 1-Q-butan-3-ol or 1-Q-pentan-3-ol is used as the reaction partner, the x0 moiety can be generated by oxidation and for this purpose, it is suitable to use oxidation means known per se, for example, chromic acid, chromium trioxide in acetic acid or the like. When esterified or etherified 1-Q-butan-3-ol or esterified or etherified 1-Q-pentan-3-ol is used as the reaction partner, hydrolysis of the esterified or etherified hydroxy group should be effected prior to oxidation. Suitable ester forming moieties are, for example, carboxylic acids, e.g. lower alkanoic acid such as acetic acid, benzoic acid, and the like; and hydrolysis of the reaction products obtained by reacting such 1-Q-butan-3-ol or 1-Q-pentan-3-ol esters is suitably conducted by alkaline ydrolysis, e.g., via the use of an aqueous alkali metal hydroxide such as aqueous sodium hydroxide. Suitable others are, for example, lower alkyl ethers, i.e. 3-methoxy, 3-ethoxy or the like; and these are suitably hydrolyzed by acid hydrolysis, e.g. via the use of an aqueous mineral acid such as hydrochloric acid, sulfuric acid or the like. When a 1-Q-butan-3-one lower alkylene ketal or a 1-Q-pentan-3-one lower alkylene ketal is used as the reaction partner, mild acid hydrolysis of the ketal moiety results in generation of the 3-oxo moiety. Finally, when 1,3-dichlorobut-3-ene or 1,3-dichloropent- 3-ene is used as the reaction partner, the 3-oxo moiety can be generated by treatment with a concentrated mineral acid, preferably a strong acid such as hydrochloric acid or sulfuric acid. It should be noted, that 1,3- dichlorobut-Z-ene and 1,3-dichloropent-2-ene may be used as reaction partners with compounds of Formulae X and XI, but not with the 17a-lower alkyl, alkenyl or alkynyl compounds of Formulae VII-IX. As will be apparent, when a reaction partner based on butane (i.e. having a four carbon atom skeleton) is utilized a compound of Formulae I-V wherein Y is hydrogen is obtained. Similarly, when a reaction partner based on pentane is utilized a compound of Formulae IV wherein Y is methyl is obtained.

In addition to the preparation of compounds of Formulae I-V from compounds of Formulae VI-XI by the use of the above mentioned reaction partners, it is also possible by the procedures of this invention to prepare compounds of Formulae I-V which, in the A-ring, in addition to containing an unsaturation between the 4- and 5-positions also contain an unsaturation between the 1- and 2-positions. Such 1,4-diene products corresponding to the compounds of Formulae I-V can be prepared from compounds of Formulae VI-XI by condensation of the latter with a reaction partner selected from the group consisting of ethinyl methyl ketone and ethinyl ethyl ketone (as well as substitutes therefor such as B-tertiary aminovinyl methyl or ethyl ketone, quaternary ammonim salts thereof, and fl-lower alkoxy-vinyl methyl or ethyl ketone). Condensation to prepare such a 1,4-diene product corresponding to the compounds of Formulae I-V is effected under the same conditions as in the condensation to prepare a compound of Formulae I-V. The so-obtained 1,4-dienes are useful in the same way as the correspondingly substituted 4-ene-compounds of Formula I-V.

The condensation is suitably effected at, below or above room temperature. For example, at the reflux temperature of the reaction medium or at ice temperature (0 C.) or below. Moreover, the condensation is suitably effected in an Organic medium. Preferably the solvent is a lower alkanol, such as methanol, isopropanol, tert-butanol, ethanol, or another non-ketonic organic solvent, such as an ether, e.g. dioxane, diethyl ether, diisopropyl ether, aromatic hydrocarbon, e.g. benzene, toluene, xylene, organic acid, such as acetic acid, or the like. Lower alkanols are the preferred solvents. It is suitable to catalyze the condensation, and this can be effected via use 10 of a catalyst such as an alkali metal lower alkoxide, for example sodium ethoxide, potassium t-butoxide, sodium tamylate, or the like, alkali metal hydroxide such as sodium, lithium or potassium hydroxide, a quaternary ammonium hydroxide, for example, a benzyl tri-lower alkyl ammonium hydroxide such as benzyl trimethyl ammonium hydroxide, para-toluene sulfonic acid, or the like.

When using a substitute for methyl or ethyl vinyl ketone, or for methyl or ethyl ethinyl ketone, the condensation should be effected under alkaline conditions. As indicated above, among such substitutes are l-tetrtiary amino-3-butanone, l-tertiary amino-3-pentanone and )3- tertiary amino-vinyl methyl or ethyl ketone. Preferred tertiary amino groups are dilower alkylamino groups such as dimethylamino, diethylamino, pyrrolidino, piperidino, morpholino, or the like. Preferred quaternary ammonium salts of such tertiary amino groups are, for example, those formed from lower alkyl halides such as methyl iodide. An exemplary fl-lower alkoxy vinyl methyl or ethyl ketone is p-rnethoxyvinyl ethyl ketone.

One aspect of this invention is the hydrogenation of desA-androst-9-en-5-ones or desA-pregn-9-en-5-ones to 95,lOB-desA-androstan-S-ones of Formulae VII-IX or to 913,IOp-desA- regnan-S-Ones of Formulae X-XI. Thus, 95, lOfi-desA-androstan-S-ones of Formula VII can be prepared via hydrogenation of desA-androst-9-en-5-ones of the formulae mo i --lower alkenyl NwR;

X (XIII) "lower alkenyl MNR X (XIV) wherein R R R and X have the same meaning as above.

Also, 9p,10B-desA-pregnan-5-ones of Formulae X and XI can be prepared by hydrogenation of desA-pregn-9-en- 5-ones of the formulae CHz-Rs HaC (XVI) wherein R';,, R R and X have the same meaning as above.

Prior to hydrogenation, the C-'20 keto group in compounds of Formulae XV and XVI or C-17 keto group in compounds of Formula XII should be protected either by involves as a first step an oxidative ring opening of ring A of thenatnral steroid. For this oxidative ring opening there can. be used as starting materials, natural steroids of conversion to the corresponding carbinol or by ketalization as described above. The hydrogenation can, however, be effected without protecting such keto groups. Y

Moreover, it should be noted that the hydrogenation,

besides inserting a hydrogen atom in each of the 9- and 10- positions, can also simultaneously effect hydrogenation of other groups in the molecule. For example, the C-keto group can be hydrogenated to the corresponding carbinol or the C-17' lower alkenyl group in compounds of Formula X III or the C-17 lower alkynyl group in compounds of Formula XIV can be hydrogenated to the corresponding O-l7-lower alkyl compounds. Compounds of Formulae VIII and IX can, in turn, be prepared from compounds of e the 3-oxo-androst-4-ene or 3-oxo-l7p pregn-4-ene series of the formula: I r

(XVII) wherein X is a substituent in the 6-position selected from the group consisting of hydrogen, lower alkyl, lower alkylthio and lower alka-noylthio or a substituent in the 7-position selected from the group consisting of hydrogen, lower alkyl, lower alkylthio, lower alkanoylthio andhalogen, and Z represents the carbon and hydrogen atoms necessary to complete the steroid D-ring, as well as the atoms in the substituents in the 16- and 17-positions as defined in Formulae I, IV, and V above.

The oxidative ring opening of a'natural steroid of Formula XVII yieldsa 5-oxo-3,SFseco-A-norandrostan-B-oic acid or a 5-oxo-3,S-seco-A-norpregnan-3-oic acid of the V formula 1 Formula VI I wherein R and R together are oxo via reac tion with a lower alkenyl or lower alkynyl Grignard reagent, with prior protection of the S-keto group, for

example,'by forming S-ketals without concurrent blocking,

of the l7-keto group. In the same manner compounds of Formulae XHI and XIV can be formed. from compounds of Formula XII wherein R and R taken together are The hydrogenation of desA-androst-9-en-5-ones of Formulae XII-XIV and of desA-pregn-9-en-5-ones of Formulae XV-XVI is one of the main features of this invention. It is effected by catalytic hydrogenation, suitably using a precious metal catalyst. Suitable precious metal catalysts are palladium, platinum, ruthenium, and rhodium, the latter two being especially preferred. It is particularly advantageous to use rhodium, for example, rhoeffected in an inert organic solvent, for example, a lowerv alkanol such as methanol or ethanol, an ether such as dioxane or diglyme, a hydrocarbon such as cyclohexane,

(XVIII) wherein X' and Z have the same meaning as above.

The oxidative ring opening of the compound of Formula XVII can be performed by a variety of methods. In a preferred embodiment is is effected by ozonolysis. The ozonolysis is suitably carried out in an organic solvent, for

example, acetic acid, ethyl acetate, methanol, chloroform, methylene chloride, or the like, or a mixture of two or more of such solvents such as ethyl acetate/acetic acid,

ethyl acetate/methylene chloride, or the like. Moreover, the ozonolysis is advantageously conducted at below room temperature. Thus, it is preferably conducted at a temperature between about C. and about 25 C. The resulting ozonides can be decomposed by conventional means,.for example, by treatment with water, hydrogen peroxide in water, aceticracid or ethyl acetate, or the like. The oxidative ring opening of a compound of Formula XVII to a compound of Formula XVIII can also be effected by other oxidation means, for example, by treatment with hydrogen'peroxide. It should be noted that, an

hexane, or the like. Lower alkanols' are preferred solvents. '1

Moreover, it is suitably conducted in the presence of an acidic or basic catalyst, for example, an alkali metal or alkaline earth metal hydroxide such as sodium hydroxide I or the like, or a mineral acid, for example, a hydrohalic acid, such as hydrochloric acid, or the like, or an organic acid such as a lower alkanoic acid, for example, acetic. acid. The reaction can be conductedat, above or below. room temperature, .for example, from about '-5 C. to,

"about 100 C. However, it is preferably conducted at a temperature between about 0 C. and about 35 C.

' As' described above, the desA-androst-9-ne-5-ones-or= desA-17Bpregn-9-en-S-ones of Formulae XII-XVI can be androst-9ren-5-ones or desA-l7l9-pregn-9-en5-ones can be prepared from steroids of the 3-oxo-androst 4-ene or 3-' oxo-17 8-pregn4-ene series by a reaction sequence which.

oxid ative ring opening by either ozonolysis'or by treatment p with hydrogen peroxide, does not require protection of any of the substituents at C-16 or 0-17." However, as

stated above, it may be desirable to protect these'substituents against some subsequent reaction in the total reaction sequence being practiced. On the other hand, the oxidative ring opening can also be effected by oxidation with chromium trioxide or via treatment with sodinmperiodate I andpotassium permanganate in potassium carbonatesolw tionand if these oxidation means are used, it is necessary to protect any secondary hydroxy groups which might be [present 'snclras a 16,173- or 2l-hydroxy group;-pref- '70? prepared from natural steroids by a variety of methods; Thus, in one embodiment of this'invention said desA-' erably, for thepurpose of this reaction, with non-aromatic I protecting groups. 7

Following the oxidative ring opening ofthe A-ring, the

i so-obtained 5-oxo-3,S-seco-A-norandrostam3-oic acid or 5-oxo-3,SQsecoA-nOrpregnan-oic acidsof Formula XVIII is converted into a mixture of a IOa-desA-androstan-S-one 13 and a IOB-desA-androstan-S-one or a mixture of a 10a: desA-pregnan-S-one and a IOfl-desA-pregnan-S-one as illustrated below:

XVIII alkali metal salt of XVIII Ha C wherein in Formulae XIX and XX, X and Z have the same meaning as above.

The compounds of Formula XIX are IOa-desA-androstan- -0nes or IOa-desA-pregnan-S-Ones, depending on the meaning of Z, and the compounds of Formula XX are 1O S-desA-andrOstan-S-ones or 10,8-desA-pregnan-5-ones. The conversion of a compound of Formula XVIII into the compounds of Formulae XIX and XX is effected by pyrolysis. In effecting the pyrolysis, it is desirable to convert the 3-oic acid of Formula XVIII into a corresponding metal salt, for example, an alkali metal salt such as the sodium or lithium salt. This conversion to a metal salt can be effected prior to pyrolysis, e.g., by treating the acid with sodium hydroxide or in situ during the course of the pyrolysis, e.g., by fusing the 3-oic acid with a mixture of sodium acetate and potassium acetate. The pyrolysis can be conducted at atmospheric pressure or in a vacuum. One preferable embodiment is to conduct the pyrolysis in a vacuum, at a temperature from about 200 C. to about 350 C. in the presence of a proton acceptor, e.g. an alkali metal or alkaline earth metal salt of a weak organic acid, for example, potassium acetate, sodium acetate, sodium phenyl-acetate, sodium bicarbonate, or the like; especially preferred is a vacuum of from about .001 to about .5 mm. Hg. Accordingly, it is advantageous to conduct the pyrolysis under alkaline conditions, i.e. at a pH greater than 7. The pyrolysis can be effected in solution or by fusion. An especially preferred method of effecting the pyrolysis is by fusion of an alkali metal salt of a weak acid, for example, an organic carboxylic acid such as a lower alkanoic acid or a phenyl-lower alkanoic acid such as phenyl-acetic acid. Another method of effecting the pyrolysis is to heat, preferably at atmospheric pressure, a solution of an alkali metal salt, such as the sodium or lithium salt, of a 3-oic acid of Formula XVIII in a basic organic solvent. The basic organic solvent should, of course, be one which is in the liquid state at the temperature at which the pyrolysis is effected. Thus, the pyrolysis can be effected at a temperature up to the boiling point of the basic organic solvent being used. Suitable basic organic solvents are, for example, nitrogen containing organic solvents such as piperidine, pyridine, isoquinoline, quinoline, triethanolamine, or the like. When utilizing this approach using a basic organic solvent it is suitable to heat to temperature between about 200 C. and about 300 C., and preferably between about 230 C. and about 260 C. A preferred basic organic solvent for the pyrolysis of a salt of a compound of Formula )QVIII to compounds of Formulae XIX and XX is quinoline. If a basic organic solvent is used which boils substantially below 200 C. at atmospheric pressure, it is suitable to conduct the pyrolysis in a sealed tube or an autoclave.

14 In another aspect, compounds of Formula XIX can be prepared from compounds of the formula (XIXA) wherein X and Z have the same meaning as above.

The compounds of Formula XIX can be prepared from compounds of Formula XIXA in the same manner that compounds of Formula XIX are prepared from compounds of Formula XVII, i.e. by oxidative ring opening of the A-ring of a compound of Formula XIXA followed by elimination of the residue of the A-ring, to yield a compound of Formula XIV. The oxidative ring opening of the compound of XIXA can be performed by ozonolysis as described above for the conversion of a compound of Formula XVII to a compound of Formula XVIII. Such ozonolysis of a compound of Formula XIXA yields a compound of the formula (XIXB) wherein X and Z have the same meaning as above, and

A is carboxy or formyl.

A compound of Formula XIXB can then be converted to a compound of Formula XIX. This removal of the residue of the A-ring, i.e. decarboxylation and deformylation, can be effected by heating in an acidic or basic medium. It is preferred to heat to the reflux temperature of the medium which is preferably an inert organic solvent such as a lower alkanol, e.g. ethanol, dioxane, ether or the like. The decarboxylation and deformylation yields mainly a compound of Formula XIX, but also a minor yield of the corresponding lOfi-isomer of Formula XXI.

Compounds of Formula XIX can also be formed from a compound of Formula XVIII via the formation of an enol-lactone of a compound of Formula XVIII, i.e. via the formation of a 4-oxo-androst-5-en-3-one or a 4-oxopregn-5-en-3-one of the formula:

HaC

HaC H Z j J l I I a H o \J XI wherein X' and Z have the same meaning as above,

' V which can then be reacted as phenyl magnesium. bromide or;phenyl lithium, to form, r

. terial..,desA-audrost-9vena5rone or 15 a with a-jGrignard reagent, such the resulting .aldol of, for example, the formula I (XXII) wherein: X and'Zhave thesame meaning as above 'which, upon treatment with an alkali metal hydroxide,

such as potassium. hydroxide, atan elevated. temperature,

for example, from about 200 C. to about 240 C., is I converted to the corresponding.la-desA:androstan-5 one 2 or -desA-pregnan-5-one of Formula XIX;

It should be'noted that though the pyrolysisof a compound, of Formula XVIII'yields boththe IDs-compoundsof Formula XX andthe IOOL'COHIPQU'IldS of Formula XIX, and though either of these'isomers can be used in the sub sequent halogenation anddehydro-halogenation steps=0fthis reaction sequence, r it'is sometimes preferable to con AtheC-l7 dihyd'roxyacetone' side chain, represented in For I dioxy 'derivativeIn 'other'cases where in a C47 oxo or 1 if reduction to the corresponding carbinol either directly 7 161- mthe reaction sequence. leading to the compounds of vert the 10/3-compound of FormulaXX into the corre f sponding IDs-compound of Formula XIX. This conversion can be effected by treating a 10B-desA-androstan-5- one or lO/i-desA-pregnan-S-one of Formula XX with any base capable'of producing a 'ca'rbanion; for example, it is suitable to use an alkali metal lower alkoxide in an Organic solvent such as a lower alkanol, for, example, sodium ethoxide in an ethanol solution or sodium methoxide in a methanol solution.

may require protection prior to the halogenationr In the case of compounds of Formulas XIX and XX containing mula wherein R is hydroxy, this protection can be effected by formation of the 17a,20;20,21-bis-methylene C-2O oxogroup is present, protection can; be effected by prior to the halogenationstep or prior to some other step Formulas XIX and XX.

v 7 ,The' halogenation can be effected with, halogenating. v H 1 agents such as bromine, sulfuryl chloride, or the like. 15

suitably'effected bytreatment. with bromine at room tem- Bromination is especially preferred. The bromination is perature or below, preferably at ice temperatureor below. Suitably it is conducted in an organic medium; for example, anr organic acid such as acetic acid; an ether such as an anhydrous ether, dioxane, tetrahydrofuran; achlorinated, organic solvent such as methylene chloride, chloroform, carbon tetrachloride; or the like; with the addition 7 of hydrogen bromide as a catalyst. When efiecting halo- :g'enation,with' sulfuryl chloride, it. is suitableto use the" same type'of organic medium as'when brominating; and

suitable catalysts are,.for example, acetic acid, benzoyl peroxide,or the like.

The subsequent dehydrohalogenation of a compound of theFormula XXIII is preferably-conducted. under mild dehydrohalogenating conditions; for example, by the use of an alkali metal carbonate (e.g. lithium. carbonate) or an alkali metal halogcnide (e-.g'. lithium halide) in anorganic solvent such as a di-lower alkyl-formamide, or with an organic base such as collidine, pyridine, or the like. The dehydrohalogenation is advantageously conducted at slightly elevated temperatures, for example, from about The above-discussed conversion via the alkali metal salt and pyrolysis of compounds of Formula XVIII to compounds of Formulas XIX and XX can be effected without protection of anyof the *substituents which might be present at C-16 or 0-17. However, if it is a desired for either 7 preceding or succeeding reaction steps ofthe total ,reac-f,

tion. sequence, the conversion of a compound of Formula XVIII to compounds of Formulas XIX and XXcan be effected with protecting groupspresent on substituents in:

the 0-16 or C-17 position. i

, As stated above, the. 10a-desA-androstan-S-ones or.l0adesA-pregnamS-ones of ,Formuia'XIX or the. IOfi-desA- androstan-S-ones of 10/8-desA-pregnan-5-ones of Formula- XX can be converted'via a two-step sequence of halogenation and dehydrohalogenation into the'desired starting maof Formulas XII, XV, and XVI.

In a preferred embodiment a 10a-desA-androstan-5-one or a 10a-desA-pregnan-5-one ofFormula-XIX is subjected to the two-step sequenceof halogenation and dehydrohalogenation. .Halogenationrof a compound of Formula XIX or a compoundof Formula, XX yields 'a mixture of corresponding halogenated compounds including one of the formula E Z Hal J Hal is a halogen atom (preferably Br or Cl).

(XXIII) V 1dqsA-pregmgfend-gng" plary dehalogenation'm'eans isxtreatment with-zineande 50 C. to about 150 0., preferably from, about 80 C. to about 120 C.

Separation .of the desired product desA-androst-9-en-5- 'oneor desA-pregn-9-en-5-'one of Formulas XII, XV and. XVI can be effected by conventional means. As indicated above the halogenation procedure may-result in halo-, genated by-products in addition to thedesired intermediate of Formula XXIII; Accordingly, the separation is preferably effected after first subjecting the reaction mixture to dehalogenating conditions in order to dehalogenate the haIogenated by-products formed by the halogenation procedure, but not dehalogenated by the dehydrohalogenation. Following such dehalog enation the reaction mix turecan then easily be separated by conventional means,

for example, by column chromatography,.to yield the de- I sired compound of Formulas XII, XV, XVI. An exemsodium acetate in an acetic acid solution at an elevated temperature, for example, about 80 C.

7 In the'case of compounds of Formulas XIX or XX whichcontaina halogen atom on acarbonatom directly adjacent to a keto group, it is preferable to protect such 'a halogen atom against dehalogenation prior. to subjecting the compound of Formulas XIX or- XX to the two step sequenceof halogenation and dehydrohalogenation of this embodiment. Such a. grouping, containing a halo- 7 gen atom on a carbon atom. directly adjacent to a keto Dehydrohalogenation of a compound'of Formula XXIII 0 group, is illustrated in a compound of Formulas IV or V wherein R or R is halogen. Thus, if 1002-" or 10fi desA- pregnan-S-Qne of Formula XIX, or H containing a 1711- 1 'or 21-halo substituent is to be subjected to the halogenaa tion-'dehydrohalogenation sequence it is,klesirable to: first effect protection of the 17w or 21'-halo substituent. This protectioncan be effected, for example, by ketalization M g. of the 20-oxo. group: V

wherein X and Z have the same meaning as above, and

As stated above, the desired desA-androst-9-en-5-ones or desApregn 9-en-5-ones starting materials can also be 'preparedfrom steroids of the 3.-oxo-androstI-4-ene or 3-oxo-17fi-pregn-4-ene series containing an ll-hydroxy substituent. In one embodiment an ll-hydroxy steroid of the formula (XXIV) wherein X and Z have the same meaning as above,

is reacted with an acid or a reactive derivative thereof to form a leaving group in the ll-position. By reactive derivative is meant, for example, a halide, e.g. a chloride, an anhydride, or the like. Though either 11 8- or 11ahydroxy starting materials can be used, it is preferable to utilize a-hydroxy compounds of Formula XXIV as starting materials. Prior to the esterification reaction, it is preferable to protect hydroxy groups present in the -16, C-17, or 0-21 position. Suitable acids for the esterification of the ll-hydroxy group, which can be used to form a leaving group in the ll-position are inorganic acids such as phosphoric acid, organic carboxylic acids such as anthraquinone B-carboxylic acid or organic sulfonic acids, for example, toluene-sulfonic acids, especially p-toluene sulfonic acid, lower alkyl-sulfonic acids such as methane-sulfonic acid and nitrophenyl-sulfonic acids, especially p-nitrophenylsulfonic acid. Especially preferred as the leaving grounp in the ll-position is a lower alkylsulfonyloxy group such as the mesoxy group. However, when it is desired to react a compound of Formula XXIV with a sulfonyloxy forming moiety, then a compound of Formula XXIV having an Hot-configuration should be used as a starting material. The above described esterification of ll-hydroxy steroid starting materials of Formula XXIV yields compounds of the formula (XXV) wherein X and Z have the same meaning as above, and

LO represents the leaving group.

In the next step of this reaction sequence, the so-formed ll-(esterified hydroxy)-compound of Formula XXV is subjected to an oxidative ring opening of the A-ring to yield the corresponding ll-(esterified hydroxy)--oxo-3,5- seco-A-norandrostan-3-oic acid or ll-(esterified hydroxy)-5-oxo-3,5-seco-A-norpregnan-3-oic acid of the formula HaC Z J y 6 HO O (XXVI) wherein X, Z and LO have the same meaning as above. The oxidative ring opening of the A-ring of a compound of Formula XXV to a compound of Formula XXVI can be effected by ozonolysis as described above for the oxidative ring opening of the A-ring of a compound of Formula XVII to a compound of Formula XVIII. Pyroylsis of the so-formed compound of Formula XXVI under the conditions described above for the pyrolysis of a compound of Formula XVIII to compounds of the Formulas XIX and XX directly yields the desired desA-androst-9-en-5-one or desA-pregn-9-en-5-one of Formulas XII, XV, XVI. Thus, pyrolysis of a compound of Formula XXVI directly results in elimination of the leaving group in the ll-position as well as a splitting olf of the residue of ring A attached to the lO-position. This procedure of starting from an 11- hydroxy steroid (preferably lla-hydroxy) of Formula XXIV and proceeding through intermediates of Formulas XXV and XXVI to compounds of Formulas XII, XV, XVI, represents a particularly elegant procedure for preparing the latter compounds. An especially preferred method of effecting the pyrolysis of a salt of a 3-oic acid of Formula XXVI is the method described above wherein the salt of the 3-oic acid is heated in a liquid basic organic solvent. Especially preferred solvents for the pyrolysis of a salt of a compound of Formula XXVI are triethanolamine and quinoline.

As indicated in the foregoing paragraph the pyrolysis of a salt of a compound of Formula XXVI involves two separate chemical attacks; one being the elimination of the ll-leaving group and the other being the splitting off of the A-ring residue. Instead of effecting these two attacks simultaneously, as described above, it is also possible to effect them sequentially by just prior to formation of the salt, effecting elimination of the leaving group of the compound of Formula XXVI. This elimination yields a A -seco acid of the formula H 0 Q H36 I V:

O X (XXVIA) wherein X and Z have the same meaning as above.

The elimination can be effected by any conventional elimination means. It is suitably conducted under alkaline conditions in an anhydrous organic solvent. Preferably, it is effected by heating, i.e. at a temperature between about room temperature and the reflux temperature of the reaction mixture. Thus, treatment of a compound of Formula XXVI with either an inorganic or organic acid or base results in the formation of the desired compound of Formula XXVIA. Preferably a Weak base is used, for example, a salt of a carboxylic acid (e.g. a lower alkanoic acid) with an alkali metal or an alkaline earth metal, for example, sodium acetate, potassium acetate, or the like. As indicated, the elimination is suitably conducted in an anhydrous organic solvent; suitable are solvents such as dilower alkyl-formamides, e.g. dimethylformamide, lower alkanoic acids, e.g. acetic acid, or the like. When a proton accepting solvent, such as dimethyformamide, is used, it itself can serve as the base for the purpose of this elimination reaction; i.e. if the solvent is basic then the elimination can be conducted without the addition of a separate basic material. Similarly, if the solvent is acidic, then the elimination can be conducted without the addition of a separate acidic material.

After the elimination is effected the A -seco acid product of Formula XXVIA can then be converted to a salt, for example, an alkali metal salt, and the so-formed salt pyrolyzed according to the conditions described above for the pyrolysis of a compound of Formula XXVI to compounds of Formulas XII, XV and XVI.

After the above-described ll-leaving group elimination and A-ring residue splitting, conducted either simultaneously or sequentially, the desired desA-9-en-5-one compounds of Formulas XII, XV and XVI can be isolated by conventional means. However, it has been found particularly suitable with compounds of Formulas XV and XVI 19 to isolate by forming the disemicarbazone of the pyrolysis product and then regenerating therefrom the desired 5,20-dione of Formulas XV or XVI, or if the 20-oxo group has been protected, for example, by reduction to a 20-hydroxy moiety, by forming the semicarbazone at the -position and then regenerating therefrom the desired 5 one compound. a a

In yet another embodiment of this invention starting material ,ll-hydroxy steroids of Formula XXIV can be directly subjected to an oxidative ring opening of the A- ring by ozonoylsis or treatment with hydroxide peroxide,

as described above for the oxidative ring opening of the A-ring ofa compound of Formula XVII to a compound of Formula XVIII. This oxidative ring opening of the A-ring of a compound of Formula XXIV yields an ll-hydroxy-S- oxo-3,5-seco-A-norandrostan-S-oic acid 3,11-lactone or an 11-hydroxy-3-oxo-3,5-seco-A-norpregnan-3-oic acid 3,11- lactone of the formula V (XXVII) wherein X and Z have the same meaning as above.

Treatment of the 3,11-lactone of Formula )QCVII with an alkali metal hydroxide such as sodium hydroxide gives the salt of the same keto acid. Withoutisolation, this salt can then be subjected to pyrolysis yielding a mixture of an ll-hydroxy-lOa-desA-androStan 5 one and an 11 hydroxy-lOJB-desA-androstan-S-one or a mixture of an 11- hydroxy-lOa-desA-pregnan-S-One and an ll-hydroxy-lOpdes-A-pregnan-S-one, as illustrated below:

wherein in Formulas XXVIII and XXIX, X and Z have the same meaning as above.

This pyrolysis of an alkali metal salt derived from a compound of Formula XXVII can be eflected under the same conditions as described above for the pyrolysis of a compound of Formula XVIII to compounds of the Formulae acids or acid derivatives and in the same manner as described above for the esterification of a compound of Formula XXIV to a compound of Formula XXV. As in that instance, it is also preferred in the present instance to form a mesoxy leaving group in the ll-position,

7 though, of course, other leaving groups as described above are useful for the instant purpose. There is thus obtained a compound of the formula H D a (XXX) wherein X, Z and LO have the same meanings as above.

The leaving group can then be eliminated from. the 11- position of a compound of Formula XXX resulting in a direct formation of a desA-androst-9-en-5-one or a DesA- pregn-9-en-5-one of Formulae XII, XV, XVI. This elimination can be effected by any conventional elimination means. It is suitably conducted under alkaline conditions in an anhydrous organic solvent. Preferably, it is effected by heating, i.e. at a temperature between about room temperature and the reflux temperature of the reaction mixture. Thus, treatment of a compound of Formula- XXX 7 with either an inorganic or organic base results in the 7 reaction; i.e. if the solvent is basic then the elimination XIX and XX; Though either the IOe-corupound of For-"f mula XXVIII or the wot-compound of Formula XXIX can be subjected to the subsequent stepsof this reaction sequence, it is suitable to utilize the lOfi-compound of Formula XXVIII. Conversion of the wot-compound of Formula XXIX to the IOB-compound of FormulaXXVIII can be effected under the same conditions as described above for the'conversion of the compound of Formula XX to a compound of Formula XIX.

In the next step of this reaction sequence, the ll-hydroxy compound of Formula XXVIII or of Formula XXIX can be subjected to esterification whereby to convert the ll-hydroxy group to a leaving group in the 11- position. This esterification can be effected with the same compound of Formula XXX. The oxidative ring opening a formation of the desired compound of Formulae XII, XV, XVI. Preferably a weak base is used, for example, a salt of a carboxylic acid (e.g. a lower alkanoic acid) with an alkali metal or an alkaline earth metal, for example, sodium acetate, potassium acetate, or the like. As indicated, the elimination is suitably conducted in an anhydrous organic solvent; suitable are solvents such as dilower alkylformamides, eg. dimethyl formamide, lower alkanoic acids, e.g. acetic acid, or the like. When a proton accepting solvent, such as dimethyl formamide, is used, it itself can serve as the base for the purpose of this elimination can be conducted without the addition of a separate basic material.

In another aspect, compounds of Formula XXX can be prepared from compounds of the formula (XXXA) wherein X, Z and LO have the same meanings as above.

The compounds of Formula XXXA can be prepared from corresponding ll-hydroxy compounds by esterification as described above for the preparation of compounds of Formula XXV from compounds of Formula XXIV. The compounds of Formula XXX can be prepared from compounds of Formula XXXA in the same manner that compounds of Formula XXX are prepared from compounds of Formula XXV, i.e. by oxidative ring opening of the A-ring of a compound of Formula XXXA followed by elimination of the residue of the A-ring to yield a of the compounds of Formula XXXA can be performed by ozonolysis as described above for conversion of a compound of Formula XXV to a compound of Formula (XXXB) wherein X, Z and LO have the same meaning as above.' A compound of Formula XXXB can then be converted to a compound of Formula XXX. This removal of the residue of the A-ring, i.e. decarboxylation, can be effected as described above for the conversion of a compound of Formula XIXB to a compound of Formula XIX.

The compounds of Formulae I-V preparable by the methods of this invention are not only pharmaceutically useful compounds as described above, but also are themselves useful as intermediates for other 9,8,10a-steroids; for example, compounds wherein X is hydrogen or lower alkyl can be modified so as to introduce unsaturation between -6 and C-7. This can be effected by dehydrogenation means, for example, by halogenation followed by dehydrohalogenation or by means of 2,3dichloro-5,6- dicyanobenzoquinone, according to known methods. Thus, for example, a 9B,10a-progesterone of Formula IV where in X is hydrogen or lower alkyl can be converted to a 913,10-pregna-4,6-dien-3,20-dione.

A further embodiment of this invention comprises the preparation of 9/3,l0u-steroids of Formulae I-V containing an ll-hydroxy substituent. This can be effected by utilizing an 1l-hydroxy-lOu-desA-androstan-S-One or 11- hydroxy-lOa-desA-pregnan-S-One of Formula XXIX or an 1l-hydroxy-lOfi-desA-androstan-S-one or ll-hydroxy-IQB- desA-pregnan-S-one of Formula XXVIII as the starting materials. It is preferred in this embodiment to use the 8-isomers of Formula XXVIII as starting materials. As a first step in this the ll-hydroxy group of the compound of Formulae XXVIII or XXIX should be protected. This is suitably effected by esterification, preferably with a carboxylic acid, for example, a lower alkanoic acid such as acetic acid, benzoic acid, or the like. Conversion of the so-obtained ll-esterified hydroxy compound then yields an ll-(esterified hydroxy)-desA-androst-9-en-5-one (i.e. a compound of Formula XII containing an ll-esterified hydroxy moiety) or an 11-esteri fied hydroxy-desA-pregn-9-en-5-one (i.e. a compound of Formulae XV-XVI containing an Ila-esterified hydroxy moiety). This conversion can be effected by halogenation followed by dehydrohalogenation, as described above for the conversion of a compound of Formulae XIX or XX to a compound of Formulae XII, XV or XVI. Catalytic hydrogenation of the so-obtained compound of the formula (XXXI) wherein X and Z have the same meaning as above, and E0 is an esterified hydroxy group as described above in this paragraph,

22 yields an ll-esterified hydroxy-desA-9/3,IOB-androstan-S- one or ll-esterified hydroxy-desA-9B,IOflregnan-S-one, of the formula H O E (XXXII) wherein X, Z and E0 have the same meaning as above.

This hydrogenation can be conducted in the same manner as described above for the hydrogenation of a compound of Formulae XII-XVI to a compound of Formulae VII, X, XI. Also, compounds of Formula XXXII containing a l7-oxo moiety can be converted to a corresponding compound containing a 17fi-hydroxy, l7a-lower alkenyl or lower alkynyl moiety by the methods described above. Also, compounds of Formula XXXII can be hydrolyzed to yield corresponding ll-hydroxy compounds of Formula XXXII, i.e. wherein E0 is hydroxy.

Condensation of the so-obtained compound of Formula XXXII or the corresponding l7fi-hydroxy, l7a-lower alkenyl or lower alkynyl compound (i.e. a compound of Formula VI containing a free or ll-esterified hydroxy group) then yields the desired end-product 9,8,l0u-steroid of Formulae I-V containing an ll-hydroxy group. Such condensation can be effected as described above for the preparation of a compound of Formulae I-V from a compound of Formulae VIXI. The so-obtained 9B,:i0d steroids containing an ll-esterified hydroxy group can be hydrolyzed to the corresponding compounds containing an ll-hydroxy group, which latter compounds are themselves useful as intermediates, for example, the l1 hydroxy group can be oxidized by methods known per se to yield corresponding ll-oxo steroids analogous to compounds of Formulas IV.

The pharmaceutically useful compounds prepared by the methods of this invention can be administered internally, for example, orally or parenterally, with dosage adjusted to individual requirements. They can be administered in conventional pharmaceutical forms, e.g. capsules, tablets, suspensions, solutions, or the like.

The following examples are illustrative but not limitative of this invention. All temperatures are in degrees centigrade. The Florisil adsorbent used infra is a synthetic magnesia-silica gel available from the Floridin Company, P. O. Box 989, Tallahassee, Fla. (of. p. 1590, Merck Index, 7th Edition, 1960). -200 mesh material was used. The moiety designated by tetrahydropyranyloxy is tetrahydro-Z-pyranyloxy. When it is stated that a procedure is effected in the cold, it should be understood that it is commenced at 0 C. Throughout this application when compounds of the pregnane series are referred to it should be understood that it is compounds of the 17,8-pregnane series that are being referred to, unless specifically indicated to the contrary, and Whether or not the compound of the pregnane series is specifically indicated as of the l7fi-series.

Example 1 A solution of 3.2 g. of 17a-ethyltestosterone in 50 ml. methylene chloride and 25 ml. of ethyl acetate was ozonized at 70 (acetone-Dry -Ice bath) until the solution was blue in color. After oxygen was passed through, the solution was evaporated at room temperature in vacuo. The syrupy residue was then dissolved in 100 ml. of glacial acetic acid, and after addition of 5 m1. of 30 percent hydrogen peroxide, left for 24 hours at 0-5. Following this time, it was evaporated to dryness, dissolved in 1500 ml. ether, and extracted with 2 N sodium carbonate solution. The alkaline extract was poured in ice cold hydrochloric acid. The resultant crystalline 170w ethyl-17flehydroxy-5-oxo- 3,5 seco-A-,norandrostan-3-oic acid was filtered, washed with waterand dried. Upon being recrystallized from acetone, it melted at 196-197".

7 Example 2 j A solution of 1.5 g. of l7a-ethyl l7phydroxy-5 oxo- 3,5-seco-A-norandrostan-3-oic acid in'100 ml. of meth anol wastitrated with 2. N sodium methoxide to'the reddish color of phenolphthaleine, and then evaporated to dryness in vacuo, giving as the residue, the sodium salt of 17a-eth'yl- 17,8-hydroxy-5-oxo-3,5-seco-A-norandrostan-1 3-oic. acid. ,5. g. of sodium-phenylacetate was heated to the residue, and the mixture pyrolyzed in vacuo 0.l mm.) at 285-295, for 2.5 hours. The sublimate was dissolvediniacetone, filtered and the filtrate concentrated in vacuo. The resultant syrupy "residue'iwas chromatographed on a 60 g. Florisil (adsorbent) column. The fractions eluted with benzene and 0.5 percent ethylacetate in benzene were combined and'gave l7a-ethyl-17fi-hydroxy-10a-desA-androstan-5one,' M.P.-9495 after re crystallization from petroleum ether. The fractions eluted with 2 percent and 5 percent ethylacetate in benzene were combined and gave 17a-ethyl-17,8:hydroxy-10fidesA-androstan-5-one, M.P. 185-1855", after two recrystallizations from petroleum ether.

Example 2a To a solution of 100 mg. of 1'Za-ethyM7B-hydroxy-l0/8 desA-androstan-S-one in 10 mL'of absolute ethanol was" added one equivalent of sodium ethoxide dissolved i115 24 Example 4 r A suspension of 262 mg. of 5 percent rhodium on alumina catalyst in a mixture of 26 ml. of 95 percent ethanol 1 and 5.25 ml. of 2 N sodium hydroxide solution was prereduced. (i.e. hydrogenated at room temperature and at-,

mospheric pressure). To this was added a solution of 2 62 mg. of l7a-ethyl-17,8-hydroxy-desA-androst-9-en-5 one in 15 ml. of 95 percent ethanol, andv the mixture then hydrogenated at atmospheric pressure and room temperature. After one mole-equivalent of hydrogen was absorbed, the reaction was stopped, the catalyst was separated by filtration, and the filtrate evaporated in vacuo.

Glacial acetic acid (1 ml.) Was added to the residue,

which was then dissolved in 1 liter of ether. The cloudy solution which resulted was washed with 2 N Na CO solution, then with Water, dried and evaporated to dryness in vacuo.,

The reaction was repeated 3 more times, and the combined products chromatographed on a Florisil (adsorbent) column. The eluates with 1 percent ethyl acetate .in benzene gave first crystallinefractions, which were 7 followed by non-crystalline fractions. The non-crystalline fractions were dissolved in 100 ml. of methylene chloride,

7 and after the addition of 2.5 ml. of 2 percent CrO in V 90 percent acetic acid, stirred overnight; The excessof chromic acid. was removed by washing the methylene chloride solution with 10 ml. of 10 percent sodium hydrogen sulfite solution, followed by washing with 2N Na CO solution and then with water. It was'then dried and evapo- .ratedin vacuo. The, residue wasidissolved in 50ml. of Ji anhydrous ethanol containing 172 mg. of sodium ethoxide,

ml. of absolute ethanol. This reaction mixture was maintained at room temperature overnight, then acidified with Example 3 1.13 g. of 17a-ethyl-17B-hydroxy-lOu-desA-androstan- S-one was dissolved in 120 ml. of anyhdrous ether (or 11.13 g. of IO/i-isomer was dissolved in 300 ml. of anhydrous ether), and after cooling in a salt-ice bath, several drops of 30 percent hydrobromic acid in acetic acid were added. This was followed by the dropwise additiorr during five minutes of 0.684 g. of bromine dissolved in 2 ml. of acetic acid. This addition was synchronized with the decoloration rate of the reaction mixture. Immediately after this, 5 ml. of a saturated solution of sodium bisulfite and 5 ml. of 2 N sodium carbonate solution were added. The mixture was then transferred into a separatory funnel, 500 ml. of ether added, ,shaken andseparated. The

ether part was washed with water, dried and evaporated. The resultant bromides were dissolved in 100 ml. of dimethylformamide, and after addition of 3 g. of lithium carbonate, the solution was heated at 100 for 45 minutes. After cooling, it was poured into one liter of ether, washed with water, 1 N hydrochloric acid, 2 N sodium carbonate, water, dried and evaporated. The residue was dissolved in 40 ml. of glacial acetic acid, 1.2 g. of sodium acetate and 1.2 g. of zinc powder added, and the soformed mixture heated 10 minutes at 80. It was then poured into one liter of ethylacetate and the resultant solution washed with saturated sodium bicarbonate, then with water, dried and evaporated. The residue was chromatographed on Florisil (adsorbent) column. The fraction with benzene and /2 percent ethylacetate in benzene gave regenerated starting material. Fractions with 1 and 2 percent ethylacetate in benzene gave l7a-ethyl-l7fi-hydroxy-desA-androst-9-en-5-one, which after sublimation (140 and 0.1 mm. Hg vacuum), was obtained as a glass. [041 -36.6 (c. =1, CHCI and left overnight. The next day, after addition of 0.5 m1. of glacial acetic. acid, the solution was evaporated in vacuo, and the residue was taken up in 1 liter of ether. The ether solution was washed with 2 N Na CO solution, then with water, dried and evaporated. The residue was chromatographed on Florisil (adsorbent) column and gave crystalline 17a-ethyl 17;3-hydroxy-desA-9;8,10B- androstan-S-one identical (by thin layer chromatography) with the crystalline material obtained in the first chromatographic separation. After two recrystallizations from ether, it melted at 142-144"; [a] 11.65 [methanol, c.=1.245 percent].

Example 5 To a solution of 132. mg. of 17a-ethyl-17p-hydroxydesA 95,105 androstan-S-one in 12.5 ml. of absolute ethanol containing 34 mg. of sodium ethoxide, 0.15 ml.

of freshly distilled methylvinyl ketone was added. The reaction mixture was then refluxed fortwo hours in a nitrogen atmosphere. After cooling the reaction mixture, 0.1 m1. of glacial acetic acid was added thereto and the resulting mixture was the poured into 1 liter of ether. The resultant ether. solution was washed with water, dried over anhydrous sodium sulfate and evaporated in vacuo.

The residue was ehromatographed on fluorescent silicagel plates, with the solvent system, 60 percentethyl acetate 40 percent heptane. The fluorescent part of the layers was extracted with ethyl acetate. The residue obtained after evaporation of ethyl acetate was first crystallized from ether-petroleum ether, then a second time from pure ether, yielding l7a-ethyl-9B,IOa-testosterone, M.P. 131- Example 6 crystallization from acetone yielded 11a-hydroxy-3,5-seco- A-nor-pregnane-S,20-dione-3-oic acid 3,1l-lactone, M.P. 253-256. [a] +193.3 c.=1, in chloroform).

Example 7 A methanolic solltion of 7.5 g. of 11u-hydroxy-3,5- seco-A-nor-pregnane-S,20-dione-3-oic acid 3,11 lactone was treated with one equivalent of 10 N sodium hydroxide solution and then evaporated to dryness. Sodium phenylacetate (26 g.) was added to the so-obtained sodium salt and the mixture pyrolyzed at 295 for two hours in vacuo. The crude sublimate was chromatographed on a silica-gel column and eluted with 10 percent ethylacetate in benzene. The amorphous solid lla-hydroxy-lOa-desA- pregnane-5,20-dione was first eluted from the column. IR- spectrum in chloroform: 3620 and 3600 cm. (OH); 1706 cm." (carbonyl gorup). NMR-spectrum in deuterochloroform: a doublet for 10a-CH at 73.5 and 80.5 c.p.s., downfield from TMS at 60 mc./sec. Further elution of the column with 10 percent ethylacetate in benzene yielded crystalline 11a-hydroxy-10/3-desApregnane-5,20- dione which was recrystallized from methylene chloridepetroleum ether, M.P. 150-152; [a] +84.0 (c.=0.5 in absolute ethanol).

Example 8 To a solution of 100 mg. of methanesulfonylchloride in 0.7 ml. of pyridine, there was added 100 mg. of Ila-hydroxy-lB-desA-pregnane-5,20 dione. The mixture Was then allowed to stand overnight at 2 (in a refrigerator), then was diluted with water (100 ml.) and extracted with chloroform (3X 150 ml.) and methylene chloride (100 ml.). The combined organic extracts were washed with water, 1 N hydrocloric acid and again with water, then dried over anhydrous sodium sulfate and evaporated in vacuo. The crystalline residue was recrystallized from ether, giving 11ot-hydroxyelOB-desA-pregnane-S,20-dione methanesulfonate, M.P. 139-140"; [a] +46 (c.=0.5 in absolute ethanol).

Example 9 A solution of 200 mg. of 11cc hydroxy IOp-desA- pregnane-5,20-dione methanesulfonate in 50 ml. of dimethylformamide was refluxed for eight hours and then evaporated to dryness. The residue was chromatographed on a Florisil (adsorbent) column. Elution was 2 percent ethylacetate/ benzene and evaporation of the eluant yielded desA-pregn-9-ene-5,20-dione in the form of colorless needles, M.P. 111-113 It was shown by mixed melting point to be identical with a sample of the same compound prepared as described in Example 12.

Example To a solution of g. of lla-hydroxy-progesterone in 150 ml. of pyridine maintained at 0, there was added 6 ml. of methanesulfonylchloride, and the reaction mixture allowed to stand overnight at 0. It was then diluted with a large excess of water and extracted with chloroform. The organic extracts were washed with 2 N hydrochloric acid and water, then dried over anhydrous sodium sulfate and evaporated in vacuo. The solid residue was recrystallized from methanol to give lla-mesyloxy-progesterone, M.P. 159.5l60; [a] +145.6 (c.=1, chloroform).

Example 11 A solution of 12 g. of 11a-mesyloxy-progesterone in 300 ml. of methylene chloride/ethyl acetate (2:1) was treated with ozone at -70 until the solution became blue in color. The excess of ozone was removed by bubbling oxygen through the reaction mixture for five minutes. Methylene chloride was then removed under reduced pressure, and the solution diluted with ethyl acetate to 200 ml. After addition of 12 ml. of percent aqueous hydrogen peroxide, the reaction mixture was then allowed to stand overnight at 2 (i.e., in the refrigerator), then evaporated to a volume of 75 ml. and diluted with 125 26 ml. of benzene. The aqueous solution, obtained by extraction with 8 parts of 75 ml. 2 N sodium carbonate followed by combining the aqueous extracts was acidified with cold concentrated hydrochloric acid to pH 2 and extracted with methylene chloride. This extract was dried over anhydrous sodium sulfate and evaporated in vacuo to dryness. The residue crystallized when triturated with ether-acetone mixture, yielding crude 11a-mesoxy-5,20-dioxo-3,S-seco- A-nor-pregnan-3-oic acid. After recrystallization from acetone-petroleum ether, M.P. 152153; [a] +47.9 (c. 1 chloroform).

Example 12 A solution of 6 g. of 11a-mesoxy-5,20-dioxo-3,5-seco- A-nor-pregnan-3-oic acid in 150 ml. of methanol was mixed with a solution of 1.5 g. of sodium carbonate in 55 m1. of water. The mixture was then transferred into a 1 liter sublimation flask, and evaporated to dryness. To the thus formed sodium salt, 20 g. of sodium phenyl acetate is added, and after closing the top part of the apparatus, this mixture was pyrolyzed at 290 and 0.02 mm. for four hours. The product, which collects on the cold finger, was dissolved in ether and filtered. The filtrate was then evaporated to dryness. Purification of the residue by chromatography on a 40 g. silica-gel column (benzene eluant) gave crystalline desA-pregn-9-ene-5,20-dione; M.P. 111- 1l3 (after recrystallization from ether). [a] +56.8 (c.=0.25 percent in methanol).

Example 13 To a solution of 1.2 g. of desA-pregn-9-ene-5,20-dione in 20 ml. of methanol maintained at 0, there was slowly added a cooled solution of 1.2 g. of sodium borohydride in 22 ml. methanol, and the resultant mixture was left for 72 hours at 0. It was then diluted with 100 ml. of water and extracted with .four 100 ml. portions of chloroform. The extract was dried over anhydrous sodium sulfate and evaporated in vacuo, yielding a colorless oily product. This product was dissolved in 250 ml. of chloroform and 6 g. of manganese dioxide was added to the solution which was then stirred for 72 hours at room temperature, filtered and the filtrate evaporated to dryness in vacuo. The residue was chromatographed on a silica-gel column and the elnates with 5 percent ethyl acetate in benzene, after concentration gave crystalline ZOB-hydroxy-desA- pregn-9-en-5-one which upon recrystallization from methylene chloride-petroleum ether formed colorless needles, M.P. 122123; [a];, 33 (c.=0.5, absolute ethanol).

Example 14 A suspension of 262 mg. of 5 percent rhodium on alumina catalyst in a mixture of 26 ml. of percent ethanol and 5.25 ml. of 2 N aqueous sodium hydroxide was hydrogenated at room temperatur and atmospheric pressure. To this was added a solution of 262 mg. of 20(3- hydroxy-desA-pregn-9-en-5-one in 15 ml. of 95 percent ethanol, and the reaction mixture then hydrogenated at room temperature and atmospheric pressure. After one mole equivalent of hydrogen was absorbed, the reaction was stopped, and the catalyst was separated by filtration. After standing overnight the filtrate was concentrated in vacuo. To the residue was added 1 ml. of glacial acetic acid, and it was then dissolved in 1 liter of ether. The cloudy solution was washed with 2 N aqueous sodium carbonate solution, then with Water, then dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. It yielded a colorless oil, which was chromatographed on a silica-gel column using 1 percent ethyl acetate in benzene as the elutant. First eluted was 20,8-hydroxy- 10a-desA-pregnan-5-one, M.P. 107108 after recrystallization from methylenechloride/petroleum ether. R.D. methanol); 1500 -3; 1400 1350 274; 1335; [0&1 1l65.

Furthermore elution yielded 20/8-hydroxy-9 3JO13-desA- pregnan-S-one as a colorless oil. R.D. (in methanol);

Example 15 A suspension of 262mg. of 5 percent rhodium on alumina catalyst in a mixture of 2 ml. of 3 N aqueous hydrochloric acid and 18 ml. of 95 percent ethanol was hydrogenated at room temperature ture and atmospheric pressure. A solution of 262 mg. of 20,8-hydroxy-desA-pregn-9- en-S-one in 5 ml. of absolute ethanol was introduced into the hydrogenation flask, and the reaction mixture was then hydrogenated at room temperature and atmospheric pressure. After one mole-equivalent of hydroegn was absorbed sure. After one mole-equivalent of hydrogen was absorbed, the reaction was stopped, the catalyst was separated by filtration, and the filtrate neutralized with 2 N aqueous sodium hydroxide solution. An excess of 5 ml. of 2 N aqueous sodium hydroxide was added and the solution allowed to stand overnight. Ethanolwas then removed by evaporation'at reduced pressure, and after addition of 1 ml. of glacial acetic acid, it was extracted with 1 liter of ether. The extract was washed with 2 N aqueous sodium carbonate solution, then with water, dried and concentrated in vacuo. It gave a colorless oil, which was chromatographed on a silica-gel column using 2 percent ethyl acetate in benzene as the elutant. The first fractions of the eluate yielded, upon concentration, 205- hydroxy-IOa-pregnan-S-One. From the immediately subsequent fraction, 20;8-hydroxy-9,B,IOB-desA-pregnan-S-one was obtained. Both products were identical with the same compounds obtained in Example 14.

Example 16 20fi-hydroxy-95J0ot-pregn-4-en-3-one is prepared by condensation. of 20 3-hydroxy-9fi,lOfi-desA pregnan-S-one with methyl vinyl ketone according to the procedure of Example 5. The product melts at 176.5178.5; [u]

143 (chloroform).

Example 17 A medium is prepared of 20 g. of Edamine enzymatic digest of lactalbumin, 3 g. of corn steep liquor and 50 g. of technical dextrose diluted to 1 liter with tap water and adjusted to a pH of 4.3-4.5. Twelve liters of this sterilized medium is inoculated with Rhizopus nigricans minus strain (A.T.C.C. 6227b) and incubated for 24 hours at 28 using a rate of aeration and stirring such that the oxygen uptake is 6.3-7 millimoles per hour per liter of Na SO according to the method of Cooper et al., Ind. Eng. Chem., 36, 504 (1944). To this medium containing a 24 hour growth of Rhizopus nigricans minus strain, 6 g. of 17a-acetoxy-progesterone in 150 ml. of acetone is added. The resultant suspension of the steroid in the culture is incubated under the same conditions of temperature and aeration .for an additional 24 hour period after which the beer and mycelium are extracted. The mycelium is then filtered, washed twice, each time with a volume of acetone approximately equal in volume to the mycelium, extracted twice, each time with a volume of methylene chloride approximately equal to the volume of the mycelium. The acetone and methylene chloride extracts including solvent are then added to the beer filtrate. The mixed extracts and beer filtrate are then extracted successively with 2 portions of methylene chloride, each portion being /2 the volume of the mixed extracts and beer filtrate, and then with'2 portions of methylene chloride, each portion being A the volume of the mixed extracts and beer filtrate. The combined methylene chloride extracts are then washed with 2 portions of a 2 percent aqueous solution of sodium bicarbonate, each portion being the volume of the combined methylene chloride extracts. The methylene chloride extracts are then dried with about 3-5 g. of anhydrous sodium sulfate per liter of solvent, and then filtered. Thesolvent is then removed from the filtrate by distillation, and the residue is dis- 28 solved in a minimum of methylene chloride, filtered and the solvent evaporated from the filtrate. The resulting crystals are then dried and washed five times, each time with a 5 ml. portion of ether per gram of crystal. The crystals are then recrystallized from ether giving 17a-acetoxy-11ahydroxy-progesterone. 17a acetoxy lla-mesoxy-prm gesterone is prepared by treatment of 17a-acetoxy-11ahydroxy-progesterone with methanesulfonyl chloride, ac

cording to the procedure of Example 10.

Example 18 17a acetoxy 5,20 dioxo mesoxy-A-nor-3,5- secopregnan-B-oic acid is prepared by ozonolysis of 17aacetoxy-llot-mesoxy-progesterone, according to the procedure of Example 11.

Example 19 17a actoxy desA pregn 9 ene-5,20-dione is pre pared from 17a-acetoxy-5,20-dioxo-1la-mesoxy-Amor- 3,5-secopregnan-3-oic acid by conversion of the latter to its sodium salt followed by pyrolysis, according to the procedure of Example 12.

Example 20 17a actoxy 20B hydroxy desA-pregn-9-en-5-one is prepared from 17tat-acetoxy-desA-pregn-9-en-5,20-dione by reduction and reoxidation according to the procedure of Example 13.

Example 21 acetoxy 20p hydroxy 9 8,10 3-desA pregnan- 5-one is prepared from 17a-acetoxy-20p3-hydroxy-desA- pregn-9-en-5-one by hydrogenation under acidic conditions in the presence of a rhodium catalyst, according to the procedure of Example 15.

Example 22 20B hydroxy 4 mthyl 95,100 pregn-4-en-3-one is prepared by condensing 20fl-hydroxy-9/8,lOfi-desA-pregnan-S-one and ethyl vinyl ketone according to the procedure of Example 5.

Example 24 1719 hydroxy 5 oxo-3,5-seco-A-nor-androstan-3-oic acid is prepared by ozonolysis of testosterone according to the procedure of Example 1.

Example 25 17 3 hydroxy 10c: desA-ndrostan-S-one and 17/3- hydroxy 10B desA-androstan 5 one are prepared. from hydroxy 5 oxo 3,5-secoeA-norandrostan- 3-oic acid by conversion of the latter to its sodium salt followed by pyrolysis, according to the procedure of Example 2.

Example 26 176 hydroxy desA androst 9 en 5 one is prepared from 175 hydroxy IOa-dCSA-aHdIOStaII-S-OIIB by bromination followed by dehydrobromination, according to the procedure of Example 3.

Example 26a DesA-androst-9-ene-5,17-dione is prepared from 17,6- hydroxy-desA-androst-9-en-5-one by oxidation of the latter with a 2 percent chromic acid solution. in 90 percent acetic acid. The so-obtained desA-androst-9-ene-5,17 dione is recrystallized from cyclohexane and melts at 123-123.5; [0L]5g9 =+83 (c.=0.1021, dioxane).

29 Example 27 A solution of 236 mg. of 175-hydroxy-desA-androst- 9-en-5-one in 40 ml. percent ethanol and 5.25 ml. 2 N aqueous sodium hydroxide solution was hydrogenated with one mole equivalent of hydrogen over 236- mg. of prereduced 5 percent rhodium on alumina catalyst. After separation of catalyst, the solution was concentrated in vacuo to dryness, and the residue taken up in one liter of ether. The ether solution was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. From the residue 175-hydroxy-95,105-desA- androstan-S-one was obtained by crystallization. M.P. 144.5-145"; [a] 22 (c.=0.103; dioxane). The 175- acetate (i.e. 175-acetoxy-95,105-desA-androstan-5-one) is obtained by acetylation of testosterone followed by ozonlysis, pyrolysis, bromination and dehydrobromination, and reduction according to the methods of Examples 24, 25, 26 and 27 respectively, and melts and 118119; [a] 28 (c.=0.103; dioxane).

Example 28 A solution of 238 mg. of 175-hydroxy-95,105-desA- androstan-S-one, 1 ml. of ethylene glycol and catalytic amount of p-toluene sulfonic acid in 100 ml. of anhydrous benzene was slowly distilled until no more water was coming over. The solution was then concentrated in vacuo to a small volume, and 175-hydroxy-95,105 desA androstan 5 one S-ethylene ketal was obtained from the residue by crystallization. M.P. 115-116"; [a] 9 (c.=0.0987; doxane).

Example 29 To a solution of 282 mg. of 175-hydroxy-95,105-desA- androstan-S-one S-ethylene ketal in 50 m1. of methylene chloride was added 1 equivalent of 2 percent chromic acid in pyridine, and the reaction mixture then stirred overnight. The reaction mixture was then washed with percent aqueous sodium hydrogen sulfite, 2 N aqueous sodium carbonate, water, then dried over anhydrous sodium sulfate and concentrated in vacuo to dryness. Crys tallization of the residue gave 95,105-desA-androstane- 5,17-dione 5-monoethylene ketal. Splitting of the ketal in acetone solution in the presence of a catalytic amount of p-toluene sulfonic acid gives 95,105-desA-androstane-5, 17-dione which melts, after recrystallization from cyclohexane, at 77.5-78"; [111 +55 (c.=0.107; dioxane).

Example 30 To a preformed solution of one mole equivalent of prop-1'-inyl lithium in 100 ml. of anhydrous liquid ammonia was added tetrahydrofuran solution of 200 mg. of 95,105 -desA androstane 5,17 dione 5-mono-ethylene ketal, and the reaction mixture stirred for two hours. After addition of one gram of ammonium chloride, cooling was discontinued, and the reaction mixture allowed to evaporate. The residue was extracted with methylene chloride, the extract was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was dissolved in 20 ml. of acetone and the catalytic amount of p-toluenesulfonic acid added, and the solution was refluxed for two hours, then poured in water and extracted in methylene chloride. The methylene chloride extract was washed with water, then dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. Crystallization of the residue gave 17a-(prop-1'- inyl)-175-hydroxy-95,105-desA-androstan-5-one.

Example 31 17a-(prop-1'-inyl) 175 hydroxy-95,10a-androstan-4- en-3-one is prepared by condensing methyl vinyl ketone with 17a-(prop-1'-inyl)175-hydroXy-95,105-desA-androstan-S-one according to the procedure of Example 5. The product melts at 164165.

Example 32 To a stirred solution of one mole equivalent of Z-methyl-prop-2-enyl magnesium bromide in ml. of ether at room temperature was added dropwise a solution of 280 mg. of 95,l'05-desA-androstane-5,17-dione 5-mono-ethylene ketal in 100 ml. of tetrahydrofuran. The reaction mixture was refluxed for one hour. After cooling in an icesalt bath, a saturated solution of sodium sulfate Was slowly added to decompose the Glignard complex. This was followed by addition of anhydrous sodium sulfate. The solution was separated by filtration and concentrated in vacuo to dryness. The solution of the residue and of a catalytic amount of p-toluene sulfonic acid in 20 ml. of acetone was refluxed for two hours, then poured in water and extracted in methylene chloride. Methylene chloride extract was washed with Water, dried over anhydrous sodium sulfate and evaporated to dryness. From the residue 17a(2-methyl-prop-2'-enyl)-175 hydroxy 95,105-desA- androstan-S-one was obtained.

Example 33 17w(2'-methyl-prop-2-enyl) 175 hydroxy-95,100:- androst-4-en-3-one is prepared from 17a-(2'-methyl-prop- 2'-enyl)-175-hydroxy 95,105 desA-androstan-S-one by condensation of the latter with methyl vinyl ketone according to the procedure of Example 5. The product melts at 106408.

Example 34 16a-acetoxy 20 ethylenedioxy-pregn-4-en-3-one is prepared by acetylation of 16a-hydroxy-20-ethylenedioxypregn-4-ene-3,20-dione with one equivalent of acetic anhydride in pyridine solution at room temperature for 2 hours, followed by concentration to dryness in vacuo. 16ot-acetoxy-ZO-ethylenedioxy 5 oxo-3,5-seco-A-norpreguan-3-oic acid is prepared by ozonolysis of 16u-acetoxy-20-ethylenedioxy-pregn-4-en-3-one according to the procedure of Example 1.

Example 35 16a-acetoxy-ZO-ethylenedioxy-10a-desA-pregnan-S-One and a acetoxy-20-ethylenedioxy-105-desA-pregnan-5- one are prepared from 16a-acetoxy-ZO-ethylenedioxy-S- oxo-3,S-seco-A-norpregnan-3-oic acid by conversion of the latter to its sodium salt followed by pyrolysis (according to the procedure of Example 2) and reacetylation with acetic anhydride and pyridine.

Example 36 16a-acet0xy 20 ethylenedioxy-desA-pregn-9-en-5-one is prepared from 16a-acetoxy-20-ethylenedioxy-10a-desA- pregnan-S-one by bromination followed by dehydrobromination, according to the procedure of Example 3.

Example 37 16a-acetoxy 20 ethylenedioxy-95,1'05-desA-pregnan- 5-one is prepared from 161% acetoxy-ZO-ethylenedioxydesA-pregu-9-en-5-one by hydrogenation under basic conditions in the presence of a rhodium catalyst, according to the procedure of Example 14.

Example 38 16a-hydroxy 20 ethylenedioxy-95,10a-pregn-4-en-3- one is prepared by condensing 16a-acetoxy-20-ethylenedioxy-desA-95,105-pregnan-5-one with methyl vinyl ketone according to the procedure of Example 5.

Example 39 35-hydroxy 16oz methyl-pregn-S-en-ZO-one ethylene ketal is prepared by ketalization of 35-hydroxy-16a-methyl-pregn-S-en-ZO-one in benzene solution with ethylene glycol using p-toluenesulfonic acid as catalyst. Pyridinechromic acid oxidation of the so-obtained 35-hydroxy-16amethyl-pregn-5-en-20-One ethylene ketal yields 16a-methyl-ZO-ethylenedioxy-pregn 4 en-3-one. 16a-methyl-20- ethylenedioxy 5 0xo 3,5-seco-A-norpregnane-3-oic acid '1dridefpyridine'prior to itsbeingworkedmp.

is prepared by ozonolysis of 16a-methyl-2O-ethyIene dioxypregn-V4-en-3-one according to the procedure of Example 1.1; V

Example 40 Y i '16a methyl-20-ethylenedioxy 10a dsA-pregnan-S- S-secor -norpregnan3-oic acid is prepared by ozonol ysis of 11e+mesoxy-16u, 17 oc-isopropylidenedioxy-progesterone, a according to the procedure of Example 11 one and 16a methyl-20-ethylenedioxy-1OE-deSAa regnaner S-one are preparedfrom"16u-rnethyl-20ethylenedioxy 5-:

oxo-3,S-seco-A-norpregnan-3 oic acid'by conversion of the latter to its sodium salt followed by pyrolysis, according to the procedure of Example 2.

' Example 41 leer-methyl 20 ethylenedioxy-desA-pregn-9-en-5-one Example 42 l6oi-methyl -20 ethylenedioiry-Qfi,lOB-desA-pregnan- 1 5-one is prepared from 160: methyl-ZO-ethylenedioxydesA-pregn -9-en-5-one by hydrogenation under basic conditions in'the presence of a rhodium catalyst, according to i the procedure of Example 14.

Example 43 one is prepared by condensing 16a-methyl-20-ethylenedioxy-9,B,IOfi-desA-pregnan-S-one with methyl vinyl ketone, according tothe procedureof Example 5. V

I Example 44 i 7 V 21-acetoxy-11a-hydroxy 20 ethylenedioxy-pregn-4- en-3-one isprepared by microbiological treatment of12I- acetoxy-Z0-ethylenedioxy pregm- 4 en-3-on'e, according to the procedure of Example 17. 21-acetoxy-11a-mesoxy- Y 20-ethylenedioxy-pregn-4 en-3-one is'prepared by treatr4-ene-3 one with methanesulfonyl chloride, accordingfto the procedure of Example 10 7 v Example 45 i I seco-A-norpregnan-3-oic acid is prepared by ozonolysisr of 21-acetoxy-1lwmesoxy-2O-ethylenedioxy pregn 4 one,

according to the procedure of Example 11.

Example Zl-acetoxy 20 ethylenedioxy-desA-pregn-9-en-S-one is prepared from 21-acetoxy-20-ethylenedioxy-1lot-mesoxy-3,5-seco A-norpregnan-3-oic acid by conversion ofthe 32 Example 5', 20 dioxo- 1 1a-mesoxy-16a,17a-isopropylidenedioxy-3,

Example 51 a V 165:,170: isopropylidenedioxydesA pregn 9-en-5,20-

dione isprepared from 5,20-dioxo-11a-mesoxy-16a,1f7aisopropylidenedioxy-3,5-seco-A-norpregnan-3-oic acid by conversion of the latter to its sodium salt, followed by pyrolysis according to the procedure of Example '12.

Example 52 H 20fl-hydroxy-16a,17a-isopropylidenedioxy-desA-pregn- 9-en-5-one is prepared from 16a,17u-isopropylidenedioxydesA-pregn 9-ene-5,20-dione by reduction and reoxidation according to the procedure of Example 13. 7

Example 53 pregnan-S-one is prepared from 20,3-hydroxy-16 1-7a -isopropylidenedioxy-dcsA-pregn 9-en-5-one by hydrogenament'of 21 acetoxy-1lwhydroxy20-ethylenedioxypregne 7 latter'to its sodium saltfollowed by pyrolysis, according to the procedure of Example 12, except that the crude product is reacetylated by treatment with acetic anhy- Example 47 tions in the presence of a rhodium catalyst,according to V r the procedure of Example 15.

a Example48 7 7 2I-hydroxy-Z0 ethyIenedioxy-918,1(la-pregn-4 en-3-one is Example 49 propylidenedioxy-progestcrone with methane sulfonyl chloride, according to the procedure of Example 10.

' j 1laamesoxy l6a;17024sopropylidehedioxy progesterone is prepared by treatment of 11a hydroxy-16a,17 -isotion according to the procedure of Example 14.

Example 54 ketone with 20 3 hydroxy-16a,l7a-is0propylidenedioxydesA-9fl,l0l3-pregnan-5-one according to the procedureof V Example 5;

Example 55 drostan 3 oic acid is prepared from 7u,17d=dirnethyltestosteronev by ozonolysis ofthelatter, according to the procedure of Example 1.

1 7 Example 56' S 70:,176: dimethyl one and 7a,17a-dimethyl lri'fi-hydroxy-IQh-desA-androstan S-onc are prepared from 7a,17a-dimethy1-'17;8-hy

droxyi-seco A-norandrostan-3 0k acid by conversion of V J the latter to its sodium salt followed by pyrolysis, according to the procedure of Example 2.

' Example 57' 7a,17a-dimethyl-1'7;8-hydroxy-desA-androst-9-en-S-one is prepared from 7oz,17a-dimethy1-1'7fl-hydroxy-10a-desA- androstan-S-one by bromination followed by dehydrobromination according to the procedure of Example 3.

a r Example 58 7u,17a dimethyl-17,8-hydroxy-desA-9/3JOfi-androstan- 5 one is prepared from 7a,,17e-dimethyl17p-hydroxydesA-androst-Q-emS-one by hydrogenation in the presence": a of a rhodiumfcatalyst', according to the procedure of Ex- 7 a ample 4.

a Example; 59

7a,17a-dimethyl-9B,met-testosterone is prepared from 7 7115171 dimethyk17p-hydroxy-desA9fi;105-androstan-5- one by condensing the latter with methyl vinyl ketone, ac-

cordin'gto the procedure of Example 5 7 Example 60'" Example 61 nan-3-oic acid is prepared from lla-mesoxy-lia-methylprogesterone by ozonolysis of the latter, according to the, V

re e es o Emma i a l7p-hydroxywIQa-desA-andrOstan-S- 1lut-mesoxy-17a-methyl-progesterone is prepared from 1lot hydroxy-17a-methyl progesterone by treatment of the latter with 'methane sulfonylchloride; according to the arprofiedure of Example 10; V V

33 Example 62 17a methyl-desA-pregn-9-ene-5,20-dione is prepared from 11oz mesoxy-17a-methyl-5,20-dioxo-3,5-seco-A-norpregnan-3-oic acid by conversion of the latter to its sodium salt followed by pyrolysis, according to the procedure of Example 12.

Example 63 20,8 hydroxy-17u-methyl-desA-pregn-9-en-5-one is prepared from 170: methyl-desA-pregn-9-en-5,20-dione according to the procedure of Example 13.

Example 64 20/3-hydroxy-l7u-methyl-9B,IOB-desA-pregnan-S-one is prepared from 170: methyl-20fi-hydroxy-desA-pregnan-9- ene-S-one according to the procedure of Example 15.

Example 65 20,8-hydroxy-17a-methyl-9 8,10a-pregn-4-en-3-one is prepared by condensing 17oz methyl 20fl-hydroxy-9fi,10/3- desA-pregnan-S-one with methyl vinyl ketone, according to the procedure of Example 4.

Example 66 A solution of 12.8 g. of 17a-methyltestosterone in 200 ml. of methylene chloride and 100 ml. of ethyl acetate was ozonized for 1 hour and minutes at 70 (acetone- Dry Ice bath) until a blue color developed. After oxygen was bubbled through, the solution was then concentrated at room temperature in vacuo. The residue was dissolved in 300 ml. of acetic acid, and after addition of 30 ml. of 30% hydrogen peroxide, the solution was left overnight at 0. It was then evaporated to dryness in vacuo, the residue taken up in ether, and the ether solution extracted with 2 N aqueous sodium carbonate (12X 50 ml.). The combined carbonate extracts were cooled in ice, and acidified with concentrated hydrochloric acid. The aqueous suspension of precipitated organic acid was extracted with methylene chloride, this extract was washed with water, dried over anhydrous sodium sulfate and evaporated giving as a colorless crystalline material l7/9-hydroxy l7u-methyl-5-oxo-3,S-seco-A-nor-androstan-3-oic acid. After recrystallization from acetone-hexane, it melted at 195-197", [a] =9.8 (c.=1.0 in chloroform).

Example 67 A solution of g. of 17,3-hydroxy-l7u-methyl-5-oxo- 3,5-seco-A-nor-androstan-3-oic acid in 250 ml. of methanol was made alkaline to phenolphthalein with sodium ethoxide, and evaporated to dryness. The residual powdery sodium salt was mixed well with 32 g. of sodium phenylacetate and 40 g. of neutral alumina (Woelm, Grade I), and the mixture heated at 290 in vacuo for 4 hours. After cooling to room temperature, a large excess of water was added, and the resultant suspension extracted with 2 liters of ether. The ether extract was washed with water, aqueous 2 N sodium carbonate solution, and again with water, dried and evaporated. This gave a sirupy residue, which by thin layer chromatograms and infrared spectra consisted of 17/3-hydroxy-17a-methyl- 10a-desA-androstan-5-one as the major and 17fl-hydroxy- 17 oz methyl 10 3 desA-androstan-S-one as the minor product.

Three additional pyrolyses were performed as described above, and the combined products so-obtained was chromatographed on a 850 g. silica gel column, using 5% ethylacetate in benzene as the eluent. This chromatography yielded 17 8-hydroxy-17m-methyl-looc-desA-androstan-S-one, which after recrystallization from petroleum ether melted at 9697, [oc] =28.2 (c.==0.5 in chloroform).

Further el-uates of the column gave product, 1713-hydroxy-17a-methyl-l0fi-desA-androstan-5-one which, when recrystallized from ether, melted at 165-167, [u] 19.8 (c.=0.5 in chloroform).

To a solution of 2.2 g. of the mixture of l7p-hydroxy- 17m-rnethyl-10a-desA-androstan-5-one and 17,8-hydroxy- 17a-methyl-IOB-desA-androstan-S-one (obtained by the above pyrolysis procedure) in 50 ml. of absolute ethanol were added 20.1 ml. of a solution prepared by dissolving 2.48 g. of sodium metal in 250 ml. of absolute ethanol. The reaction mixture was stirred overnight at room temperature. It was then acidified with 2 ml. of glacial acetic acid, and evaporated to dryness. The residue was extracted in ether (1 liter) and the ether extract washed with water, dried, and evaporated. The residue was crystallized from petroleum ether giving a quantitative yield of 17,8-hydroxy-l7u-methyl-lOa-desA-androstan-S-one.

Example 68 To a solution of 11.2 g. of 17fi-hydroxy-17u-methyl- 10a-desA-androstan-5-one in 1260 ml. of anhydrous ether, stirred and cooled in an ice-salt bath, were added first several drops of 30% hydrogen bromide in acetic acid, then dropwise a solution of 7.16 g. of bromine in 20 ml. of glacial acetic acid. The rate of addition of the bromine solution was synchronized with the rate of disappearance of excess bromine. After bromination was complete, 53 ml. of 10% sodium hydrogen sulfite solution and 53 ml. of aqueous 2 N sodium carbonate solution were added to the reaction mixture while stirring. The ether layer was then-separated, washed with water, dried, and evaporated to dryness in vacuo. The residue was dissolved in 250 ml. of dimethylformamide, and heated with 7.5 g. of lithium carbonate at 100 for 45 minutes. After cooling, 2 liters of ether were added and the ether solution washed with water, 1 N hydrochloric acid, and then again with water, dried and evaporated. The residue was dissolved in 200 ml. of glacial acetic acid, 12.6 g. of sodium acetate and 12.6 g. of Zinc powder were added and the mixture heated for ten minutes at After cooling to room temperature, the reaction mixture was filtered, and evaporated. The residue was dissolved in ethylacetate, and washed with saturated sodium bicarbonate solution, then with water, dried and evaporated. The so-obtained residue was chromatographed on a silica gel column using 10% ethylacetate in benzene as the eluent which gave first 17,8- hydroxy-17a-methyl-IOa-desA-androstan-S-one, followed by 175 hydroxy 17a methyl-desA-androst-9-en-5-one. After recrystallization from ether, the latter compound melted at l03104, [a] =63.2 (c.=0.5 in chloroform).

Example 69 A suspension of 1.25 g. of 5% rhodium on alumina catalyst in a mixture of 130 ml. of 95% ethanol and 26 ml. of 2 N sodium hydroxide was prereduced. To this was then added a solution of 1.25 g. of 17fl-hydroxy-17umethyl-desA-androst-9-en-5-one in 75 ml. of 95% ethanol, and then the mixture was hydrogenated at atmospheric pressure and room temperature. After one mole equivalent of hydrogen was absorbed, the reaction was stopped, the catalyst was removed by filtration, and the filtrate evaporated in vacuo. To the residue 5 ml. of glacial acetic acid was added, the so-formed mixture then dissolved in 2 liters of ether, and the resultant cloudy solution was washed with water, then dried and evaporated. The residue was dissolved in 50 ml. of methylene chloride and oxidized with 5 ml. of 2% chromic acid in acetic acid until green color of reaction mixture. After then being washed with sodium hydrogen sulfite solution 2 N sodium carbonate solution and water, the reaction mixture was dried over sodium sulfate and evaporated. The residue was chromatographed very slowly on a 50 g. silica gel column, with 5% ethylacetate in benzene, and followed with thin layer chromatography. First, 17,9-hydroxy-l7m-methyl-9a,10m-desA-androstan-5-one was eluted. After a minor amount of mixed material, 17,8-hydroxy- 17 methyl 9p,10p-desA-androstan-5-one was eluted.

.densationof thellatter with methyLvinyl fketone,accord The product melts melted at94-96".

Example 70 After recrystallization from etherpetroleum ether,

tration and dried, then disolvedin 135 ml. of absolute ethanolfand after addition of '9 ml. of aqueous 2 N 17u-methyl-9B,lOcetestQsterone is prepared from 17a.

ing" to "the procedure of Example SI at 128-129".

Example 71 one in 100 ml. methylene chloride and 50 ml. of ethylacetate was ozonized at 70. After methylene chloride was removed by distillation in vacuo, the residual S0111? tion was diluted to 100 ml. with ethylacetate. To this ml. of 30 percent hydrogen peroxide was added and;

left overnight at room temperature. The reaction mixture was concentrated to dryness in vacuo, the residue taken up in 1 liter of ether, and the resulting solution extracted times with 50 ml. portions of 2 N aqeous sodium carbonate. The carbonate extract was then, acidified with ice-cold concentrated hydrochloric acid. 'The precipitated product was separated by filtration, and

crystallized to give 1le 205-diacetoxy-5-oxo-3,5-seco-A- nor-pregnan-B-oic acid.

Example 721 g A methanolic solution of 5 g. of 11 a,20;3-diacetoxy-5- oxo-3,5-seco-A-nor-pregnan-3-oic acid was treated with one-half mole equivalent of sodium'carbonate, and evaporated to dryness in vacuo. Potassium acetate (5 g.) was added to the residue which was then pyrolyzed at 295? and 0.02 mm. The sublimate was chromatographed on a silica-gel column to give 11a,20,B-diacetoxy-lOfi-desA- pregnan-S-one.

Example 73 Bromination and dehydrobromination starting with 11a,20fl-diacetoxy-lOfi-desA-pregnan-S-one according to the procedure of Example 3, gave 11,2O 8-diacetoxy:

desA-pregn-9-en-5-one.

Example 74 10 A solution of 6 g. of 110:,205-diacetoxy-pregn-4-en-3-r sodium hydroxide, boiled for 1 hr. The reaction mixture was, concentrated in vacuo to a small volume, and diluted 'With 11750111 1. :ofetheri: The ethersolution was' washed 1? with water; driediover anhydroussodium sulfate,- and r coneentratedin vacuoto dryness. The residuewas'crystallized from ether-petroleum ether, to give 17wethy1-17fihydroxy-10wdeSA-andrOstan-S-one, M.P. 8990.

Example'78.

3-( l7B-hydroxy-5-oxo 3,S-seco-A-nor-androstan-17w yl-3-oic acid)-propionic acid lactone is prepared by' ozonolysis of 3-(3-ox0-17B-hydroxy-androst-4-en-17a- .yl)-propionic acid lactone, according to the procedure of Examplel'.

Example 79 Example 80 3-(l7fl-hydroxy-5-oxo-desA androst-9-en-17a-yl)-propionic acid lactone is prepared from 3-(17B-hydroxy-5- oxo-IOu-desA-androstan-l7a-yl)propionic acid lactone by 'bromination followed by dehydrobromination, according to the procedure of Example 3.

. Example 81 3- 17 fl-hydroxy-5-oxo-9p, 10,8 desA-androstan-17wyl) propionic acid lactone is prepared from 3-(l7fi-hydroxy- 5-oxo-desA-androst 9-en-l7ayl)-propionic acid lactone by hydrogenation in the presence of a rhodium catalyst,

according to the procedure of Example 4.

Hydrogenation of 11a,20,3-diacetoxy-desA-pregn-Q-en-' 5-one in ethanolic hydrochloric acid over 5 percent rhodium on alumina catalyst at room temperature and atmospheric pressure according to the procedure of Example 15 gave 11a,20p-diacetoxy-9,B,lflfl-desA-pregnan-S- one.

Example 75 11a,20/8-diacetoxy-9B,IOB-desA-pregnan-S-one was bydrolyzed in methanol solution with one mole equivalent of potassium carbonate to give 1la,20fl-dihydroxy-9B, IOB-desA-pregnan-S-one.

Example 76 Condensation of 11a,20fl-dihydroxy-9,8,IOB-desA-pregnan-S-one with methyl vinyl ketone according to the procedure of Example 5 gave 11a,20B-dihydroxy-913,l0a-

V pregn-4-en-3-one.

Example 77 A solution of 3 g. of 17a-ethyl-17fi-hydroxy-androsta- 1,4-dien-3-one in ml. of methylene chloride and. 25

Example 82 3-(17p'hydroxy 3-0XO-9;3,10m androst-4en-17a-yl)- propionic acid lactone is prepared by condensing 3-(175- hydroxy-5-oxo-9fl,IOB-desA androstan-17a-yl)-propionic acid lactone with methyl vinyl ketone, according to the procedure of Example 5.

Example 83 17a,20;20,2l-bis methylenedioxy 11a mesyloxypregn-4-en-3-one is prepared by treatment of 17u,20;29', 21-bis-methylenedioxy-1 lu-hydroxy-pregn-4-en-3-one with methanesulfonyl chloride according to the procedure of Example 10.

Example 84 17a,20;20,21-bis methylenedioxy-lla-mesyloxy-S-oxo- 3,5-seco-A-norpregna-3-oic acid is prepared by ozonolysis of l7a,20;20,2l-bis-methylenedioxy-1la-mesyloxy-pregn- 4-en-3one according to the procedure of Example 11.

Example 85 17u,20;20,21-bis methylenedioxy desA-pregn-9-en-5- one is prepared from 17a,20;20,2l-bis-methylenedioxy- 11a.-mesyloxy-5-oxo-3,5-seco-A-norpregnan-3-oic acid by conversion of the latter to its sodium salt followed by ml. of ethyl acetate was ozonized at '-70' till it be-- came blue. After'evaporaation' to dryness, the residue was. dissolved in ml. of glacial acetic acid containing 5:

ml. of 30 percent hydrogen peroxide, and set at room temperature for 2 days. The reaction mixture was concentrated to dryness and the residue dissolved in one,

liter of ether. The ether solution was then extracted 10 times with 25 ml. portions of aqueous 2 N sodium carbonate solution, and the carbonate extracts were acidified.

with ice-cold concentrated hydrochloric acid. The noncrystalline precipitate containing 17-a-ethyl-17;8-hydroxy- 1Oa-carboXy-desA-androstan-S-one was separated by filpyrolysis, according to the procedure of Example 12.

Example86 17a,20;20,21 bis methylenedioxy 9,6,10p-desA-pregnan-S-one is prepared from 17a,20;20,ZI-bis-methylenedioxy-desA-pregn-Q-en-Swne-by hydrogenation in the presence of a rhodium catalyst according to the procedure of Example 14.

Example 87 17a,20;20',21 bis methylenedioxy 95, l0a-pregn-4-en 3-one is prepared by condensing methylvinyl ketone with 37 17a,20;20,21 bis methylenedioxy-9 3,10fi-desA-pregnan- 5-one, according to the procedure of Example 5.

Example 88 20B hydroxy 95,100: pregna-1,4-dien-3-one was prepared by condensation of 20fi-hydroxy-9B,lOB-desA-pregnan-S-one with 1 equivalent of methyl ethinyl ketone in boiling benzene solution, catalyzed by sodium hydride.

Example 89 One ml. of Jones reagent (0.04 mole CrO is added to 200 mg. of 17B-hydroxy-9 3,IOB-desA-androstan-S-one in 20 m1. of acetone at -10. The mixture is then left for 15 minutes at room temperature, and 5 ml. of ethanol then added. The resulting suspension is evaporated to dryness in vacuo, water is added to the residue and the undissolved moiety taken up in ether. The ether phase is then washed with a solution of sodium bicarbonate and then water, dried over sodium sulfate and evaporated to dryness. There is so obtained an oil which crystallizes upon the addition of a small portion of petroleum ether. The so-obtained crystals of 9B,10 8-desA-androstane-5,17- dione melt, after recrystallization from cyclohexane, at 77.5-78; [a] ==+55 (c.'=0.107, dioxane); R.D. in dioxane (c.=0.107%): A in m ([a]-va1ue in 550 (+70); 400(+297); 350(+798); 320(+2968) max.; 300(+467); 299(); 290(1890).

Example 90 A solution of 250 mg. of 17fi-hydroxy-9fi,IOB-desA-androstan-S-one dissolved in 2.5 ml. of pyridine and 2.5 ml. of acetic anhydride, is left at room temperature for 18 hours. The mixture is then evaporated to dryness at 80/ 11 mm., the residue taken up in ether, and the ether phase washed with 1 N hydrochloric acid, sodium bicarbonate and water, and then dried over sodium sulfate. After filtration and evaporation of the ether, the residue is then treated with a small quantity of petroleum ether yielding crystals of l7B-acetoxy-9B,IOB-desA-androstan-S-one which, upon recrystallization from methanol, melt at 118-119"; [a] =28 (c.=0.103%, dioxane); R.D. in dioxane (c.=0.103%): x in mg ([a]-value in 400 (30); 356 (0); 350 (+10); 313 (+449) max.; 307 (+374) min.; 305 (+380) max.; 300 (+224); 293 (0); 280 (-652).

Example 91 A solution of 250 mg. of 17fi-acetoxy-9,[3,l0fl-desA- androstan-S-one in 60 ml. of 95% methanol containing 144 mg. of potassium hydroxide is refluxed for 60 minutes. The resulting mixture is evaporated to dryness in vacuo, water added to the residue and the suspension extracted with ether. The ether phase is washed with water, dried over sodium sulfate, filtered off, the solvent removed and the crystalline residue then crystallized from a small volume of cyclohexane, yielding crystals of l7fl-hydroxy- 9 3,105-desA-androstan--one which upon being recrystallized from ethylacetate melt at 144.5145; [M =22 (c.=0.103, dioxane), R.D. in dioxane (c. =0.l03); x in ma ([u]-value in 400 (+7); 390 (0); 350 (+52); 313 (+571) max.; 307 (+492) min.; 305 (+504) max.; 300 (+324); 293 (0); 290 (-202).

Example 92 A solution of 10 g. of 11B-formyloxy-androsta-1,4- diene-3,17-dione in 100 ml. of acetic acid was ozonized at 0 until thin layer chromatography did not show any starting material. The reaction mixture was then poured into 100 ml. of water and the mixture was then heated to 100 for 30 minutes. The mixture was then concentrated in vacuo and treated with 50 ml. of saturated sodium bicarbonate solution. The undissolved material was extracted with 100 ml. of ether. The extract was chromatographed on silica gel using methylene chloride. The eluates were concentrated and gave, on addition of hexane, 115- formyloxy 105 desA-androstane-S,17-dione, M.P. 117- 117.5 (recrystallized from acetone-cyclohexane), [M =93 (dioxane).

Example 93 By hydrolysis of 1lp-formyloxy-10.5-desA-androstane- 5,17-dione in 2% methanolic potassium hydroxide there is obtained 1lfi-hydroxy-IOE-desA-androstan-S,17-dione, which melts at 154; [oc] =+96 (dioxane).

Example 94 250 mg. of 1lfi-hydroxy-IOE-desA-androstane-S,17- dione and 25 0 mg. of p-toluene sulfonic acid monohydrate in 20 ml. of benezne were refluxed in a nitrogen atmosphere for 6 hours. The reaction mixture was then washed with an aqueous solution of sodium bicarbonate and then with water, dried over sodium sulfate, filtered and evaporated to dryness. The residue was then chromatographed over silica gel (5 g. in dichloromethane. Triturating the residue obtained from the first 250 ml. eluted, yielded crystals of desA-androst-9-ene-5,17-dione, which upon recrystallization from cyclohexane melted at 123-1235".

Example 95 The compound, 1lfl-formyloxy-S,17-dioxo-3,5-seco-A- norandrostan-3-oic acid is prepared from llB-formyloxyandros-4-ene-3,l7-dione by ozonolysis according to the procedure of Example 11. The so-obtained product melts at 220221; [a] =+107 (dioxane).

Example 96 3.7 g. of the sodium salt of 11fl-formyloxy-5,17-dioxo- 3,S-seco-A-nor-androstan-3-oic acid and 12 g. of sodium phenylacetate are fused together in vacuo (0.1 torr). When the bath temperature reaches 220 the molten mass begins to decompose. The bath is then heated further (Within 30 minutes) to a temperature of 290. Once this temperature has been reached the mixture is left for another 10 minutes at the initial pressure of 0.1 torr. The distilled material is then chromatographed over 30 g. of aluminum oxide (activity grade 3). Elution with a total of 200 ml. of petroleum ether-benzene (2:1), followed by evaporation of the solvent and trituration of the residue in the presence of petroleum ether, yields desA-androst-9- ene-5,17-dione which upon recrystallization from cyclohexane melts at 123-1235; [a] =+83 (c.=0.1021, dioxane).

Example 97 2OB-acetoxy-5-oxo-3,5-seco-A-nor-pregnan-3-oic acid is prepared by ozonolysis of 20 8-acetoxy-pregn-4-en-3-one according to the procedure of Example 1.

Example 98 A solution of 15.15 g. of ZOfl-acetoxy-S-oxo-3,5-seco-A- nor-pregnan-3-oic acid in 250 ml. of 75% methanol containing 10 g. of potassium hydroxide was refluxed for 2 hours. The methanol was then removed in vacuo and the residue was dissolved in 100 ml. of water. The solution was chilled to 0 and acidified to ml. of water. The solution was chilled to 0 and acidified to Congo red by the addition of 20% hydrochloric acid. There was thus ob-- tained 20fl-hydroxy 5 oxo-3,S-seco-A-nor-pregnan-3-oic acid, M.P. 181-182", [u] =13 (dioxane).

A solution of 4.7 g. of 20fi-hydroxy-5 oxo-3,S-seco-A- nor-pregnan-3-oic acid in 100 m1. of methanol was neutralized with'l N sodium methylate solution against phenolphthalein. The solution was then evaporated and the residue, consisting of 20B-hydroxy-5-oxo-3,S-seco-A- nor-pregnan-3-oic acid sodium salt, Was refluxed with 100 ml. of quinoline for 8 hours. The cooled mixture was poured on a mixture of g. of ice and 100 ml. concentrated hydrochloric acid and extracted with ether. The ether extract was worked up and the oily residue was chromatographed on silica gel. Elution with methylene chloride gave 10a-desA-pregnane-5,20-dione, M.P. 126- 127 (crystallized from isopropyl ether), [u] -=82 V (dioxane Elution with.

104l04.5 (crystallized from ethenhexane),

' [a] -10' (dioxane). The fractions obtained with,

acetonewere: evaporated and the'oily residuef'was dissolved in 40 mini;

acetone. The solution was treated with '3 ml. of Jonesmethylene chloride containing 10% reagent (0.004 mole CrO at and kept at. the same .mflhyletid zsh ri icontaisin 1 '1% acetone gave fi-h ydroxy-iOa-desA-pregnan-S-orie,'

temperature for 10 minutes. After the addition of 5 mlw V of methanol, the solution wasevaporatedand the residue].

was diluted with water and extracted with ether. The ether extract was worked up and gave 10a-desA-pregnane- 5,20-dione.

Example 99 20,8-hydroxy-desA-pregn-9-en S-one is prepared from first added with vigorous stirring at room temperature,

75 ml. of 0.8% potassium permanganate and thereafter simultaneously within minutes l350 ml. of 7%.sodium metaperiodate solution and 100 ml. of 0.8% potassium V permanganate solution. Another 1080 ml. of 7% sodium ZOfl-hydroxy-lOa-desA-pregnan-S-one by bromination fol- V lowed by dehydrobromination, according to the procedure tion, from methylene chloride-petroleum'ether, melts at Examplelqfl,

5,20-dioxo-3,S-seco-A-nor-pregnan- 3 oie acid is prepared by ozonolysis of progesterone according to thepro icedureiernxarn le "i 7 r I 'Example 101' IOa-desA-pregna 5, 20 dime and 10B-desA-pregnan-:,:.

5,20-dione are prepared from 5,20-diOXO-3,S-SGCO-PknOf- V pregnan-3-oic acid by conversion of the latter. to its cedure of Example 2. 7 7 1 Example 102 I The'cornpound, desA-pre-gn 9-ene-5,20 dioneis prepared t from 10wdsA-pregna-SQO-dione by ibromination followed by dehydrobromination according to the procedure of Example 3.. The so-obtained product, after :recrystallizae.

tion from ether, melts at- 111.113.., a 7

' Example 103 15 rnl.:of0.8% potassium'permanganate solution was added .to a mixture of ll g. of;20-tetrahydropyranyl0XY-a pregn-4-en-3-one, 500 ml. of anazeotropic mixture of 1 tertiary butanol and water, 7 g. of potassium carbonate,

30 sodium salt followed by pyrolysis, according to the pro solutionwithvigorousstirring at room temperature. 250

ml. of 7% sodium metaperiodate and 20 mLof 0.8%

potassium permanganate solution were then simultane-- ously added within 15. minutes. To-the so-obtainedasus" V pension, 220 ml. of 7% sodium metaperiodate. solution and, inorder to. keep the mixture violet in color, 1 5 ml;

of 0.8% potassium permanganate solution were then added in the course of 30 minutes; Thernixture was thenf stirred for' 9,0 'rninutes, filtered over a filter aid} (Hyfl'o) 55, and the residue was washed with 100 ml. of tert. .butanol-j,

waterazeotrope. The filtrate rwaslevaporated invacuo at and the-residue;diluted;with 1 50 ml. of Water.

acid to Congo red, and the resultant oily material taken up in 150 ml. of methylene chloride. The organic extract was washedwith Water, dried; andevaporated and the 1-2% i ethanol as the elution agents- There wasthus ob- Example 104 To a solutionof 35.8 g. of a mixture of 20aand 20,85 hydroxy-pregne4-en-3-one in 50 ml. of anhydrous benzene, there were added ml. of 1% p-toluenesulfonic acid in benzene and then 35 ml. of dihydropyramTherer action mixture'was allowed to stand atroom, tempe'ra-,

turefor 16 hours, washed With 2% aqueous sodium biphous powder.

20 ml. of water and 120 ml. of 7% sodium metape'riodate:

Y (dioxane).

metaperiodatesolution and 1001 ml. of 0.8% potassium permanganate solution were then added within 45 minutes.

The reaction mixture was then stirred for 1 hour, filtered over a filter aid (Hyflo) and the residue was washed with 250. ml. of tert. butanol-water azeotrope. The filtrate was of ExamplofirThe so-obtained'Troduct,afterrecrystalliza evapomteda the. residue' k n .up. .iu.'.800,.ml, .-0f '---T and filtered. The alkaline filtrate waschilled to 0, acidi fied with cold 20% hydrochloric acid and extracted with m ethylene chloride. After,workiugllp,,the extractafiorded ainixturefl'of 200iand 20B-tetrahydropyranyloxyd-oxo- 3,5-seco-A-nor-pregnan-3-oic acid as a viscous oil. This a I ,foilwas dissolved in 30 0 .rn-l. of methanol and; neutralized t with l Njlithium methylatei 'Thesolution was evaporated to dryness in vacuo. The oily residue was dissolved in 300 2 'ml. of benzene, evaporated again and, dried .at 11. mm.

Hg and for 2 hours. There. was obtained; a mixture 7 of the lithium salts of 20- and 20fi-tetrahydropyranyloxy-5-ox0-3,S-seco-A-noppregnan oic acid as an. anion Example 105. V

' 'A solutionof 9 'g. of 20fi-tetrahydropyranyloxy-S-oxo- 3,S-seco-Amonpregnzin-Brole acid.in.100 mlaof methu "anolwas neutralized with l N lithium methylate solution against phenolphthaleine, followed by evaporation in vacuo to dryness. The so-obtaiued residue was taken up in benzene, and the benzene evaporated .yieldinggZOfl-tetrm hydropyranyloxy5-oxo-3.5-secosAenor-pregnan 3 oic acid lithium salt as a send-crystalline powder.

5 g. of this lithium salt, 7.5 g. of anhydrous sodium acetate and 7.5 g.,of anhydrous potassium. acetate were I mixed and pyrolyzed' at 0.02-0'1 mm. Hg and 290 for 4 'hours. The distillate was chromatographed' onqsili'ca gel using methylene chloride. and methylene chloride contain-- ing 0.5.1% acetone as theelution agents. The fractious were evaporated and gave on treatment with ether-here ane 20,3 tetrahydropyranyloxyl0a-desA-pregnane5-one, M.P. 12 5.5-127 (crystallized fromrnethanol) a sr The oily part of the evaporation residue containing besides the latter compound the'cornp'ound 20B-tetrahydro- .pyranyloxy-l0fi-desA-pregnan-5-one1 ethanol. 2 After" the 1 addition of 10ml. of waterand' 200 mg. of p-toluenesulfonic acid monohydrate, the solution was refluxed for 60 minutes and evaporated in vacuo. The residuewasthen treated withwater and extracted with ether; Theether extract was worked up and gave 20;9-hyd-roxy-lOa-desA-v pregnan-S-one, M.P. 104.5105 (crystallized from ether- Example lO 7 p 250 mg. of 20a tetrahydropyranyloxy-l'OwdeSA-pregnan-S-one was dissolvedin 8 ml. of ethanol and after the: addition of 1 ml; of waterand '15 mg. of .p-toluenesul- I fonic acid monohydrate refluxed for 1 hour. The reaction mixture was then evaporated and the residue taken up in ether. The ether extract was worked up and gave 2013- 'hydroxy+IOu-desA-pregnan-S-one, M.P. 104.5-" (crys:

tallized from ether-hexane).

Example 107 

